VCV000580488.42 - ClinVar

NM_022168.4(IFIH1):c.2016del (p.Asp673fs)

Germline

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.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

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

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022168.4(IFIH1):c.2016del (p.Asp673fs)

Variation ID: 580488 Accession: VCV000580488.42

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2q24.2 2: 162277443 (GRCh38) [ NCBI UCSC ] 2: 163133953 (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	Oct 10, 2018	Oct 8, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022168.4:c.2016del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071451.2:p.Asp673fs	frameshift
NM_022168.4:c.2016delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_022168.3:c.2016del
NC_000002.12:g.162277443del
NC_000002.11:g.163133953del
NG_011495.1:g.46087del
LRG_1235:g.46087del
LRG_1235t1:c.2016del	LRG_1235p1:p.Asp673fs

... more HGVS ... less HGVS

Protein change

D673fs

Other names

Canonical SPDI

NC_000002.12:162277442:T:

Functional
consequence

The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele
frequency (GMAF)

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

The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00024

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00024

The Genome Aggregation Database (gnomAD) 0.00028

The Genome Aggregation Database (gnomAD), exomes 0.00033

Trans-Omics for Precision Medicine (TOPMed) 0.00044

Links

OMIM: 606951.0013

dbSNP: rs773033563

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.
IFIH1		-	-	GRCh38 GRCh37	1406	1433

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.
Aicardi-Goutieres syndrome 7 Singleton-Merten syndrome 1	Benign (1)	criteria provided, single submitter	Jan 25, 2024	RCV000704039.11
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 1, 2024	RCV001091997.24
Singleton-Merten syndrome 1	Likely benign (1)	criteria provided, single submitter	May 28, 2019	RCV000986844.2
Multisystem inflammatory syndrome in children	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV001779064.6
Aicardi-Goutieres syndrome 7	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV001731900.6
Immunodeficiency 95	Uncertain significance (2)	criteria provided, single submitter	Feb 17, 2023	RCV001844227.3

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.	More information 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.
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Singleton-Merten syndrome 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135986.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818287.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Uncertain significance (Nov 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003926073.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023	Comment: Observed as a homozygous variant in a patient with very early onset inflammatory bowel disease (Cananzi et al., 2021); Published functional study demonstrates that variant … (more) Observed as a homozygous variant in a patient with very early onset inflammatory bowel disease (Cananzi et al., 2021); Published functional study demonstrates that variant significantly reduces MDA5 protein activity and results in a truncated protein; however, conditions associated with pathogenic variants in IFIH1 are typically gain of function (Cananzi et al., 2021); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 34185153) (less)
Uncertain significance (Feb 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 95 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041277.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Benign (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aicardi-Goutieres syndrome 7 Singleton-Merten syndrome 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000832972.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Likely pathogenic (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248325.25 First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024	Comment: IFIH1: PVS1:Strong, PM2, PM3:Supporting Number of individuals with the variant: 2
Pathogenic (Mar 07, 2022)	no assertion criteria provided Method: literature only	IMMUNODEFICIENCY 95 Affected status: not provided Allele origin: germline	OMIM Accession: SCV002102822.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (1) PubMed: 34185153 Comment on evidence: In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with immunodeficiency-95 (IMD95; 619773), Cananzi et al. (2021) identified a homozygous 1-bp deletion (c.2016delA, NM_022168) … (more) In 3-year-old girl (patient 1), born of consanguineous Moroccan parents, with immunodeficiency-95 (IMD95; 619773), Cananzi et al. (2021) identified a homozygous 1-bp deletion (c.2016delA, NM_022168) in exon 10 of the IFIH1 gene, resulting in a frameshift and premature termination (Asp673IlefsTer5) in the Hel2i domain. It was predicted to result in nonsense-mediated mRNA decay or produce a truncated protein lacking important functional domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. The mutation was found at a low frequency in the gnomAD database (2.99 x 10(-4)). In vitro functional studies using a luciferase reporter assay showed that mutant IFIH1 failed to activate the IFNB1 (147640) promoter following stimulation, consistent with a loss-of-function effect. In addition to recurrent and severe infections, including with CMV, the patient also had very early-onset inflammatory bowel disease (VEOIBD) in the first weeks of life. (less)
Likely benign (Jan 02, 2020)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV001984543 appears to (...more) Source: NCBI	Aicardi-Goutieres syndrome 7 Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984543.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
risk factor (Nov 14, 2021)	Flagged submission flagged submission Method: research Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV002014774 appears to (...more) Source: NCBI	Multisystem inflammatory syndrome in children Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002014774.1 First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Observed as a homozygous variant in a patient with very early onset inflammatory bowel disease (Cananzi et al., 2021); Published functional study demonstrates that variant significantly reduces MDA5 protein activity and results in a truncated protein; however, conditions associated with pathogenic variants in IFIH1 are typically gain of function (Cananzi et al., 2021); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 34185153)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.	Cananzi M	Human genetics	2021	PMID: 34185153

Text-mined citations for rs773033563 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_022168.4(IFIH1):c.2016del (p.Asp673fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs773033563 ...