rs201283129
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PS1PM2BP4_Strong
The NM_000215.4(JAK3):c.1503G>T(p.Gln501His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_000215.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAK3 | NM_000215.4 | c.1503G>T | p.Gln501His | missense_variant | 11/24 | ENST00000458235.7 | |
JAK3 | XM_047438786.1 | c.1503G>T | p.Gln501His | missense_variant | 11/24 | ||
JAK3 | XM_011527991.3 | c.1503G>T | p.Gln501His | missense_variant | 11/14 | ||
JAK3 | XR_007066796.1 | n.1553G>T | non_coding_transcript_exon_variant | 11/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAK3 | ENST00000458235.7 | c.1503G>T | p.Gln501His | missense_variant | 11/24 | 5 | NM_000215.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152048Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251496Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135922
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.0000646 AC XY: 47AN XY: 727246
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152048Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74260
ClinVar
Submissions by phenotype
Acute megakaryoblastic leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Dec 26, 2014 | - - |
Leukemoid reaction Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 06, 2020 | Variant summary: JAK3 c.1503G>T (p.Gln501His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1503G>T in individuals affected with Severe Combined Immunodeficiency Syndrome has been reported although it has been reported in patients with AML (example, Sato_2008, Yamashita_2010). Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect in relation to the established mechanism of SCID (Sato_2008, Yamashita_2010). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in germline state to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 04, 2022 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 501 of the JAK3 protein (p.Gln501His). This variant is present in population databases (rs201283129, gnomAD 0.02%). 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: 376114). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt JAK3 protein function. Experimental studies have shown that this missense change affects JAK3 function (PMID: 18397343). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at