ClinVar Genomic variation as it relates to human health
NM_000215.4(JAK3):c.2164G>A (p.Val722Ile)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000215.4(JAK3):c.2164G>A (p.Val722Ile)
Variation ID: 134573 Accession: VCV000134573.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.11 19: 17834887 (GRCh38) [ NCBI UCSC ] 19: 17945696 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 9, 2014 Oct 8, 2024 Apr 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000215.4:c.2164G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000206.2:p.Val722Ile missense NC_000019.10:g.17834887C>T NC_000019.9:g.17945696C>T NG_007273.1:g.18105G>A LRG_77:g.18105G>A LRG_77t1:c.2164G>A LRG_77p1:p.Val722Ile P52333:p.Val722Ile - Protein change
- V722I
- Other names
- NM_000215.4(JAK3):c.2164G>A
- Canonical SPDI
- NC_000019.10:17834886:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00359 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00297
1000 Genomes Project 0.00359
The Genome Aggregation Database (gnomAD) 0.00743
Trans-Omics for Precision Medicine (TOPMed) 0.00761
The Genome Aggregation Database (gnomAD), exomes 0.00862
Exome Aggregation Consortium (ExAC) 0.00865
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00946
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 | ||
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HI score
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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. |
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JAK3 | - | - |
GRCh38 GRCh37 |
1231 | 1244 |
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. |
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not provided (1) |
criteria provided, single submitter
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Sep 19, 2013 | RCV000121262.12 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000418338.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000436031.2 | |
Benign (5) |
reviewed by expert panel
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Apr 3, 2024 | RCV000558788.18 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV001357996.16 | |
JAK3-related disorder
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Benign (1) |
no assertion criteria provided
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Jan 28, 2024 | RCV003915209.2 |
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. |
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. |
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Benign
(Apr 03, 2024)
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reviewed by expert panel
Method: curation
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004809132.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Comment:
NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile). The filtering allele frequency (the lower threshold … (more)
NM_000215.4(JAK3):c.2164G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 722 (p.Val722Ile). The filtering allele frequency (the lower threshold of the 95% CI of 12957/1180016) of the c.2164G>A variant in JAK3 is 0.01082 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Additionally, 120 adult homozygous occurrences are reported in gnomAD v4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and B2_Supporting (VCEP specifications version 1). (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001287909.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Jun 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000513302.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 24728327, 29921932, 10982185, 19282076, 21228398, 26182690, 27884173, 14615376, 33040328)
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Likely benign
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604052.2
First in ClinVar: Mar 08, 2017 Last updated: Feb 20, 2024 |
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Benign
(Aug 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033656.10
First in ClinVar: Sep 16, 2023 Last updated: Oct 08, 2024 |
Comment:
JAK3: BP4, BS1, BS2
Number of individuals with the variant: 12
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Likely benign
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807031.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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T-B+ severe combined immunodeficiency due to JAK3 deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000638318.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005210749.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Lymphoblastic leukemia, acute, with lymphomatous features
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505698.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Acute megakaryoblastic leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505697.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553619.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The JAK3 p.Val722Ile variant was identified in dbSNP (ID: rs3213409), Cosmic (FATHMM predicted neutral; score=0.23), LOVD 3.0 and ClinVar (classified as likely benign by GeneDx … (more)
The JAK3 p.Val722Ile variant was identified in dbSNP (ID: rs3213409), Cosmic (FATHMM predicted neutral; score=0.23), LOVD 3.0 and ClinVar (classified as likely benign by GeneDx and ARUP Laboratories and as benign by Invitae for severe combined immunodeficiency). The variant was also identified in control databases in 2370 of 282750 chromosomes (21 homozygous) at a frequency of 0.008382 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 263 of 10368 chromosomes (freq: 0.02537), European (non-Finnish) in 1573 of 129108 chromosomes (freq: 0.01218), Other in 68 of 7226 chromosomes (freq: 0.00941), Latino in 179 of 35434 chromosomes (freq: 0.005052), South Asian in 143 of 30616 chromosomes (freq: 0.004671), European (Finnish) in 90 of 25118 chromosomes (freq: 0.003583), African in 53 of 24934 chromosomes (freq: 0.002126) and East Asian in 1 of 19946 chromosomes (freq: 0.00005). The V722I variant was identified in the compound heterozygous state in 1/10 patients with severe combined immunodeficiency (SCID) (Roberts_2004_PMID:14615376). Another study identified the variant in the heterozygous state in 1/14 patients with SCID (Schumacher_2000_PMID:10982185). The V722I variant has also been identified somatically in mutliple cancers, including acute myelogenous leukemia, natural killer T-cell lymphoma, acute lymphoblastic leukemia and lung tumors and has been suggested to be an acitivating mutation (Van Allen_2015_PMID:26014096; MacConaill_2014_PMID:25157968; Bergmann_2014_PMID:24446122; Riera_2011_PMID:21599579; Yin_2015_PMID:25146434). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val722 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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Benign
(Jan 28, 2024)
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no assertion criteria provided
Method: clinical testing
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JAK3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004729929.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074686.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less)
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-04-27
Testing laboratory interpretation: Benign
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085433.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Activating alleles of JAK3 in acute megakaryoblastic leukemia. | Walters DK | Cancer cell | 2006 | PMID: 16843266 |
Complete genomic organization of the human JAK3 gene and mutation analysis in severe combined immunodeficiency by single-strand conformation polymorphism. | Schumacher RF | Human genetics | 2000 | PMID: 10982185 |
http://docm.genome.wustl.edu/variants/ENST00000458235:c.2164G>A | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a8274608-4e6d-42b9-a92a-a14282ba2d2a | - | - | - | - |
Text-mined citations for rs3213409 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.