VCV000427078.13 - ClinVar

NM_015909.4(NBAS):c.2524G>T (p.Val842Phe)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (1); Uncertain significance (3)

4 out of 4 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_015909.4(NBAS):c.2524G>T (p.Val842Phe)

Variation ID: 427078 Accession: VCV000427078.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p24.3 2: 15424368 (GRCh38) [ NCBI UCSC ] 2: 15564492 (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	May 22, 2017	May 25, 2025	Nov 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015909.4:c.2524G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056993.2:p.Val842Phe	missense
NR_052013.3:n.2554G>T		non-coding transcript variant
NC_000002.12:g.15424368C>A
NC_000002.11:g.15564492C>A
NG_032964.1:g.141981G>T

... more HGVS ... less HGVS

Protein change

V842F

Other names

p.V842F

Canonical SPDI

NC_000002.12:15424367:C:A

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.

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

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA345889621 dbSNP: rs1085307944 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.
NBAS		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	2888	2985

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.
not provided	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Feb 3, 2022	RCV000489731.12
Infantile liver failure syndrome 2	Uncertain significance (1)	criteria provided, single submitter	Jun 13, 2022	RCV002280120.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 26, 2024	RCV005056068.2

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.
Uncertain significance (Feb 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002128879.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 26073778 Comment: show This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 842 of the NBAS protein (p.Val842Phe). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with recurrent acute liver failure (PMID: 26073778). ClinVar contains an entry for this variant (Variation ID: 427078). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Likely pathogenic (Dec 07, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000577709.6 First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023	Comment: show In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26073778, 26578240, 26541327) (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

Uncertain significance (Jun 13, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Infantile liver failure syndrome 2	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002568419.2 First in ClinVar: Sep 03, 2022 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: maternal Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: maternal Affected status: yes Number of individuals with the variant: 1 Clinical Features: Birth length greater than 97th percentile (present) , Retrognathia (present) , Joint hypermobility (present) , Liver failure (present) , Mild postnatal growth retardation (present) , Hypertriglyceridemia (present) , Hepatomegaly (present) , Elevated circulating hepatic transaminase concentration (present) , Decreased circulating vitamin D concentration (present) Zygosity: 1 Compound Heterozygote Age: 10-19 years Sex: female Tissue: blood

Uncertain significance (Nov 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005725684.2 First in ClinVar: Feb 16, 2025 Last updated: May 25, 2025	Publications: PubMed (1) PubMed: 26073778 Comment: show Variant summary: NBAS c.2524G>T (p.Val842Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2524G>T has been reported in the literature in at-least one individual affected with Liver Failure Acute Infantile (example, Haack_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26073778). ClinVar contains an entry for this variant (Variation ID: 427078). Based on the evidence outlined above, the variant was classified as uncertain significance. (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

Comment:

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 842 of the NBAS protein (p.Val842Phe). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with recurrent acute liver failure (PMID: 26073778). ClinVar contains an entry for this variant (Variation ID: 427078). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26073778, 26578240, 26541327)

Comment:

Variant summary: NBAS c.2524G>T (p.Val842Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2524G>T has been reported in the literature in at-least one individual affected with Liver Failure Acute Infantile (example, Haack_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26073778). ClinVar contains an entry for this variant (Variation ID: 427078). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.	Haack TB	American journal of human genetics	2015	PMID: 26073778

Text-mined citations for rs1085307944 ...

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 May 25, 2025