rs200624610
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000215.4(JAK3):c.2324G>A variant in JAK3 is a missense variant predicted to cause substitution of arginine by cysteineat amino acid 775 (p.Arg775Cys). The filtering allele frequency (the upper threshold of the 95% CI of 55/1113096) of the c.2323C>T variant in JAK3 is 0.00003886 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID JAK3 VCEP threshold (<0.000115) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160228/MONDO:0010938/121
Frequency
Consequence
NM_000215.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JAK3 | NM_000215.4 | c.2323C>T | p.Arg775Cys | missense_variant | Exon 17 of 24 | ENST00000458235.7 | NP_000206.2 | |
JAK3 | XM_047438786.1 | c.2323C>T | p.Arg775Cys | missense_variant | Exon 17 of 24 | XP_047294742.1 | ||
JAK3 | XR_007066796.1 | n.2373C>T | non_coding_transcript_exon_variant | Exon 17 of 20 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000134 AC: 2AN: 149022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251358Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135898
GnomAD4 exome AF: 0.0000450 AC: 61AN: 1356984Hom.: 0 Cov.: 40 AF XY: 0.0000312 AC XY: 21AN XY: 673964
GnomAD4 genome AF: 0.0000134 AC: 2AN: 149022Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1AN XY: 72744
ClinVar
Submissions by phenotype
T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2025 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 775 of the JAK3 protein (p.Arg775Cys). This variant is present in population databases (rs200624610, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 134574). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt JAK3 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg775 amino acid residue in JAK3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28916186, 31440277, 32445296; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Apr 03, 2024 | The NM_000215.4(JAK3):c.2324G>A variant in JAK3 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 775 (p.Arg775Cys). The filtering allele frequency (the upper threshold of the 95% CI of 55/1113096) of the c.2323C>T variant in JAK3 is 0.00003886 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID JAK3 VCEP threshold (<0.000115) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at