VCV000812649.27 - ClinVar

NM_016146.6(TRAPPC4):c.454+3A>G

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (13); Likely pathogenic (1)

14 out of 15 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016146.6(TRAPPC4):c.454+3A>G

Variation ID: 812649 Accession: VCV000812649.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119020256 (GRCh38) [ NCBI UCSC ] 11: 118890966 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 22, 2020	Jun 20, 2026	Dec 11, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_016146.6:c.454+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001318486.2:c.136+939A>G		intron variant
NM_001318488.2:c.454+3A>G		intron variant
NM_001318489.2:c.292+3A>G		intron variant
NM_001318490.2:c.325+3A>G		intron variant
NM_001318492.2:c.139+3A>G		intron variant
NM_001318494.2:c.175+1286A>G		intron variant
NC_000011.10:g.119020256A>G
NC_000011.9:g.118890966A>G

... more HGVS ... less HGVS

Protein change

Other names

IVS3DS, A-G, +3

Canonical SPDI

NC_000011.10:119020255:A:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00023

The Genome Aggregation Database (gnomAD) 0.00025

The Genome Aggregation Database (gnomAD) 0.00026

Links

ClinGen: CA6311452 OMIM: 610971.0001 dbSNP: rs375776811 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TRAPPC4		-	-	GRCh38 GRCh38 GRCh37	83	124

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Pathogenic/Likely pathogenic (13)	criteria provided, multiple submitters, no conflicts	Dec 11, 2025	RCV001003468.27
Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies	Pathogenic (1)	criteria provided, single submitter	Nov 16, 2020	RCV001267711.2
not provided	Pathogenic (1)	criteria provided, single submitter	-	RCV001281626.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 16, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (Autosomal recessive inheritance)	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001445963.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Publications: PubMed (3) PubMed: 31794024‚ 32125366‚ 32901138 Comment: show The homozygous c.454+3A>G variant in TRAPPC4 was identified by our study in 1 individual with early-infantile neurodegenerative syndrome. This individual along with at least another 22 affected individuals from 16 families were reported in the literature (PMID: 32901138, 31794024, 32125366). This variant has also been identified in 0.04% (50/128792) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375776811). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. In addition, this variant has also been reported in ClinVar (Variation ID#: 812649) and has been interpreted as pathogenic by OMIM. Of the at least 23 affected individuals, all were homozygotes, which increases the likelihood that the c.454+3A>G variant is pathogenic (PMID: 32901138, 31794024, 32125366). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 31794024). However, these types of assays may not accurately represent biological function. RNAseq analysis performed on fibroblast cells from an affected patient shows alternative splicing in 59% of the reads and predicted to lead to skipping of exon 3 (PMID: 32901138). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive early-infantile neurodegenerative syndrome. ACMG/AMP Criteria applied: PS3, PM3, PP1_strong (Richards 2015). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001468957.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Sep 09, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512575.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: show ACMG classification criteria: PS3 supporting, PS4 strong, PM3 moderate, PP1 strong (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Geographic origin: Brazil

Pathogenic (May 04, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Mendelics Accession: SCV002519895.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 02, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (Autosomal recessive inheritance)	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV002557974.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 31794024 Comment: show Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant has been shown to cause nonsense-mediated decay (NMD) and loss of protein (PMID: 31794024). (P) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been shown to result in exon 3 skipping causing a frameshift (p.(Leu120Aspfs*9; intron 3 of 4; PMID: 31794024). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (68 heterozygotes, 0 homozygotes). (P) 0508 - In-silico predictions for abnormal splicing are conflicting. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple unrelated families with early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy (PMID: 31794024). (P) 0901 - Strong evidence for segregation with disease. The variant was shown to segregate with disease in three independent families (PMID: 31794024). (P) 1001 - Strong functional evidence supporting abnormal protein function. Fibroblasts from an affected homozygous individual showed impaired TRAPP complex assembly and golgi trafficking (PMID: 31794024). (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 16, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003799173.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: show PM4, PP1, PS3_Very Strong (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV004009636.1 First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023	Observation: 1 Collection method: research Allele origin: biparental Affected status: yes more Observation 1 Collection method: research Allele origin: biparental Affected status: yes Number of individuals with the variant: 1 Clinical Features: Brain atrophy (present) , Severe intellectual disability (present) , Developmental regression (present) , Delayed speech and language development (present)

Pathogenic (Apr 14, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (Autosomal recessive inheritance)	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001432141.2 First in ClinVar: Sep 14, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: yes Number of individuals with the variant: 1 Clinical Features: Spasticity (present) , Profound global developmental delay (present) , Postnatal microcephaly (present) , Optic disc pallor (present) , Optic atrophy (present) , Obstructive sleep apnea syndrome (present) , Infantile spasms (present) , Hypertonia (present) , Hip dysplasia (present) , Generalized myoclonic seizures (present) , Dysphagia (present) , Developmental regression (present) , Cortical visual impairment (present) , Cerebral atrophy (present) , Brisk reflexes (present) Zygosity: 1 Homozygote Age: 0-9 years Sex: female Ethnicity/Population group: Causasians Tissue: blood

Pathogenic (Feb 05, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Dasa Accession: SCV002073779.2 First in ClinVar: Feb 10, 2022 Last updated: Apr 13, 2025	Publications: PubMed (3) PubMed: 31794024‚ 32125366‚ 32901138 Comment: show Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 32901138) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 812649 PMID: 32125366; 31794024; 32901138; 31794024) - PS4. The variant is present at low allele frequencies population databases (rs375776811 – gnomAD 0.002563%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.454+3A>G was detected in trans with a pathogenic variant (PMID: 32125366; 31794024; 32901138; 31794024) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32901138; 31794024). - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil

Likely pathogenic (Oct 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Revvity Omics, Revvity Accession: SCV003812198.3 First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Institute of Human Genetics, Heidelberg University Accession: SCV005438269.2 First in ClinVar: Dec 22, 2024 Last updated: Apr 13, 2025 Comment: secondary finding	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: female

Pathogenic (Aug 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines 2015 PMID 25741868)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	OLLIN Analises Genomicas, OLLIN Accession: SCV007520886.1 First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026	Publications: PubMed (3) PubMed: 31794024‚ 32125366‚ 32901138 Comment: show The variant present at the non-canonical splicing site (chr11:119020256A>G), located in intron 3 (of 5 exons), is reported in gnomAD v4.1 non-UKB with an allele frequency of 0.027%, in ClinVar (VCV000812649.24) and in the scientific literature, also in homozygous state segregating with the phenotype, in individuals with neurodevelopmental disorders (PMID: 32901138, 31794024, 32125366). In silico analysis and functional studies suggest that this variant affects protein function (PMID: 32901138). According to currently available evidence, this variant has been classified as pathogenic (PS3, PS4, PM2_P, PM3_S, PP1, PP3). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil

Pathogenic (Dec 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (Autosomal recessive inheritance)	Variantyx, Inc. Accession: SCV007593728.1 First in ClinVar: May 16, 2026 Last updated: May 16, 2026	Publications: PubMed (2) PubMed: 31794024‚ 32901138 Comment: show This is an intronic variant in the TRAPPC4 gene (OMIM: 610971). Pathogenic variants in this gene have been associated with autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy. This variant leads to a splicing defect that results in skipping of exon 3 and a loss of the intact TRAPPC4 transcript (PMID: 32901138, 31794024) (PVS1). It has been reported in the homozygous state in many unrelated affected individuals (PMID: 32901138) (PM3) and has a 0.0621% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy.No other variant of clinical significance was identified in the TRAPPC4 gene. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Oct 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	3billion Accession: SCV007611750.1 First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026	Publications: PubMed (2) PubMed: 31794024‚ 32901138 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.038%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.52 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 32901138). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 32901138). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000812649 /PMID: 31794024). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: exome sequencing

Pathogenic (Feb 28, 2023) N Not contributing to aggregate classification	no assertion criteria provided	NEURODEVELOPMENTAL DISORDER WITH EPILEPSY, SPASTICITY, AND BRAIN ATROPHY	OMIM Accession: SCV001161770.3 First in ClinVar: Feb 22, 2020 Last updated: Mar 18, 2023	Publications: PubMed (2) PubMed: 32125366‚ 32901138 Van Bergen, N. J. Personal (more...) Van Bergen, N. J. Personal Communication. 2020. Melbourne, Australia Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In 7 children from 3 unrelated families with neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA; 618741), Van Bergen et al. (2020) identified a … (more) In 7 children from 3 unrelated families with neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA; 618741), Van Bergen et al. (2020) identified a homozygous A-to-G transition (c.454+3A-G, NM_016146.5) in intron 3 of the TRAPPC4 gene, resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was found 68 times in heterozygous state in the gnomAD database (frequency of 0.0002419), but never in homozygosity. Analysis of fibroblasts derived from 1 patient confirmed the splicing defect, with almost complete loss of the wildtype transcript and increased production of an aberrant transcript, suggesting an incompletely penetrant splicing defect. Western blot analysis showed some production of the wildtype protein, but at significantly decreased levels compared to controls; a truncated protein was not detected, consistent with nonsense-mediated mRNA decay of the mutant transcript. Fibroblasts derived from 1 patient showed overall decreased levels of fully-assembled TRAPP complexes compared to controls. Haplotype analysis was not consistent with a founder effect, but rather suggested a mutational hotspot. One additional affected deceased individual did not have DNA tested, but most likely carried the same homozygous mutation. In 23 patients from 17 unrelated families with NEDESBA, Ghosh et al. (2021) identified homozygosity for the c.454+3A-G mutation in exon 3 of the TRAPPC4 gene. The mutation was identified by whole-exome or whole-genome sequencing. The minor allele frequencies of the c.454+3A-G mutation in sequencing databases was high, e.g., 0.024% in gnomAD (v.2.1.1), 0.054% in 1000 Genomes Project, and 0.033% in NHLBI Exome Sequencing Project; however, no shared haplotype was identified in their or previously studies families. RNA sequencing in skin fibroblasts from 1 patient (patient 15) revealed partial exon 3 skipping of TRAPPC4 due to use of a cryptic splice donor site, which was predicted to result in a premature stop and nonsense-mediated decay. In a 1 year and 7-month-old girl with NEDESBA, who was born to parents Indian origin without reported consanguinity, Kaur et al. (2020) identified homozygosity for the c.454+3A-G mutation in exon 3 of the TRAPPC4 gene. The mutation, which was found by exome sequencing, was present in heterozygous state in the parents. (less)

Comment:

The homozygous c.454+3A>G variant in TRAPPC4 was identified by our study in 1 individual with early-infantile neurodegenerative syndrome. This individual along with at least another 22 affected individuals from 16 families were reported in the literature (PMID: 32901138, 31794024, 32125366). This variant has also been identified in 0.04% (50/128792) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375776811). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. In addition, this variant has also been reported in ClinVar (Variation ID#: 812649) and has been interpreted as pathogenic by OMIM. Of the at least 23 affected individuals, all were homozygotes, which increases the likelihood that the c.454+3A>G variant is pathogenic (PMID: 32901138, 31794024, 32125366). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 31794024). However, these types of assays may not accurately represent biological function. RNAseq analysis performed on fibroblast cells from an affected patient shows alternative splicing in 59% of the reads and predicted to lead to skipping of exon 3 (PMID: 32901138). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive early-infantile neurodegenerative syndrome. ACMG/AMP Criteria applied: PS3, PM3, PP1_strong (Richards 2015).

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant has been shown to cause nonsense-mediated decay (NMD) and loss of protein (PMID: 31794024). (P) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been shown to result in exon 3 skipping causing a frameshift (p.(Leu120Aspfs*9; intron 3 of 4; PMID: 31794024). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (68 heterozygotes, 0 homozygotes). (P) 0508 - In-silico predictions for abnormal splicing are conflicting. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple unrelated families with early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy (PMID: 31794024). (P) 0901 - Strong evidence for segregation with disease. The variant was shown to segregate with disease in three independent families (PMID: 31794024). (P) 1001 - Strong functional evidence supporting abnormal protein function. Fibroblasts from an affected homozygous individual showed impaired TRAPP complex assembly and golgi trafficking (PMID: 31794024). (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Comment:

Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 32901138) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 812649 PMID: 32125366; 31794024; 32901138; 31794024) - PS4. The variant is present at low allele frequencies population databases (rs375776811 – gnomAD 0.002563%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.454+3A>G was detected in trans with a pathogenic variant (PMID: 32125366; 31794024; 32901138; 31794024) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32901138; 31794024). - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The variant present at the non-canonical splicing site (chr11:119020256A>G), located in intron 3 (of 5 exons), is reported in gnomAD v4.1 non-UKB with an allele frequency of 0.027%, in ClinVar (VCV000812649.24) and in the scientific literature, also in homozygous state segregating with the phenotype, in individuals with neurodevelopmental disorders (PMID: 32901138, 31794024, 32125366). In silico analysis and functional studies suggest that this variant affects protein function (PMID: 32901138). According to currently available evidence, this variant has been classified as pathogenic (PS3, PS4, PM2_P, PM3_S, PP1, PP3).

Comment:

This is an intronic variant in the TRAPPC4 gene (OMIM: 610971). Pathogenic variants in this gene have been associated with autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy. This variant leads to a splicing defect that results in skipping of exon 3 and a loss of the intact TRAPPC4 transcript (PMID: 32901138, 31794024) (PVS1). It has been reported in the homozygous state in many unrelated affected individuals (PMID: 32901138) (PM3) and has a 0.0621% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy.No other variant of clinical significance was identified in the TRAPPC4 gene.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.038%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.52 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 32901138). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 32901138). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000812649 /PMID: 31794024). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.	Ghosh SG	European journal of human genetics : EJHG	2021	PMID: 32901138
Recurrent bi-allelic splicing variant c.454+3A>G in TRAPPC4 is associated with progressive encephalopathy and muscle involvement.	Kaur P	Brain : a journal of neurology	2020	PMID: 32125366
Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.	Van Bergen NJ	Brain : a journal of neurology	2020	PMID: 31794024
Van Bergen, N. J. Personal Communication. 2020. Melbourne, Australia	-	-	-	-

Text-mined citations for rs375776811 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 20, 2026