VCV000636814.9 - ClinVar

NM_001290043.2(TAP2):c.1417G>A (p.Val473Ile)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001290043.2(TAP2):c.1417G>A (p.Val473Ile)

Variation ID: 636814 Accession: VCV000636814.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.32 6: 32830662 (GRCh38) [ NCBI UCSC ] 6: 32798439 (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	Jul 27, 2019	Aug 18, 2024	Oct 17, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001290043.2:c.1417G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001276972.1:p.Val473Ile	missense
NM_000544.3:c.1417G>A	NP_000535.3:p.Val473Ile	missense
NM_018833.3:c.1417G>A	NP_061313.2:p.Val473Ile	missense
NC_000006.12:g.32830662C>T
NC_000006.11:g.32798439C>T
NG_009793.4:g.13109G>A
LRG_167:g.13109G>A
LRG_167t1:c.1417G>A	LRG_167p1:p.Val473Ile
LRG_167t2:c.1417G>A	LRG_167p2:p.Val473Ile

... more HGVS ... less HGVS

Protein change

V473I

Other names

Canonical SPDI

NC_000006.12:32830661:C:T

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

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.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD) 0.00005

Links

dbSNP: rs765178638 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.
TAP2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	359	429

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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 8, 2018	RCV000788754.3
MHC class I deficiency	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 17, 2022	RCV001056446.8

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.
Uncertain significance (Oct 08, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927983.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel
Uncertain significance (May 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MHC class I deficiency 1 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001711948.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Publications: PubMed (2) PubMed: 10560675‚ 7517574 Comment: TAP2 c.1417G>A (rs765178638) is rare (<0.1%) in a large population dataset (gnomAD: 12/277972 total alleles; 0.004%; no homozygotes) and has not been reported in the … (more) TAP2 c.1417G>A (rs765178638) is rare (<0.1%) in a large population dataset (gnomAD: 12/277972 total alleles; 0.004%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be tolerated, while one predicts that it would be damaging. The valine residue at this position is evolutionarily conserved in many of the species assessed, however an isoleucine is present at this position in a subset of species. We consider the clinical significance of TAP2 c.1417G>A to be uncertain at this time. (less)
Uncertain significance (Oct 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	MHC class I deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001220889.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 473 of the TAP2 protein (p.Val473Ile). … (more) This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 473 of the TAP2 protein (p.Val473Ile). This variant is present in population databases (rs765178638, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 636814). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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)
Uncertain significance (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MHC class I deficiency 1 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV001468442.2 First in ClinVar: Jan 09, 2021 Last updated: May 06, 2023	Comment: TAP2 NM_000544.3 exon 8 p.Val473Ile (c.1417G>A): This variant has not been reported in the literature but is present in 0.009% (1/10262) of Ashkenazi Jewish alleles … (more) TAP2 NM_000544.3 exon 8 p.Val473Ile (c.1417G>A): This variant has not been reported in the literature but is present in 0.009% (1/10262) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-32798439-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:636814). Of note, 3 species carry this variant Isoleucine (Ile) as wild type (Prarie Vole, Chinese Hamster, Lizard); however, evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005188890.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024

Comment:

TAP2 c.1417G>A (rs765178638) is rare (<0.1%) in a large population dataset (gnomAD: 12/277972 total alleles; 0.004%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be tolerated, while one predicts that it would be damaging. The valine residue at this position is evolutionarily conserved in many of the species assessed, however an isoleucine is present at this position in a subset of species. We consider the clinical significance of TAP2 c.1417G>A to be uncertain at this time.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 473 of the TAP2 protein (p.Val473Ile). This variant is present in population databases (rs765178638, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 636814). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:

TAP2 NM_000544.3 exon 8 p.Val473Ile (c.1417G>A): This variant has not been reported in the literature but is present in 0.009% (1/10262) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-32798439-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:636814). Of note, 3 species carry this variant Isoleucine (Ile) as wild type (Prarie Vole, Chinese Hamster, Lizard); however, evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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
Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules.	Moins-Teisserenc HT	Lancet (London, England)	1999	PMID: 10560675
Homozygous human TAP peptide transporter mutation in HLA class I deficiency.	de la Salle H	Science (New York, N.Y.)	1994	PMID: 7517574

Text-mined citations for rs765178638 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001290043.2(TAP2):c.1417G>A (p.Val473Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs765178638 ...