19-17835160-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000215.4(JAK3):c.1970G>A(p.Arg657Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R657W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000215.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAK3 | NM_000215.4 | c.1970G>A | p.Arg657Gln | missense_variant | 15/24 | ENST00000458235.7 | |
JAK3 | XM_047438786.1 | c.1970G>A | p.Arg657Gln | missense_variant | 15/24 | ||
JAK3 | XR_007066796.1 | n.2020G>A | non_coding_transcript_exon_variant | 15/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAK3 | ENST00000458235.7 | c.1970G>A | p.Arg657Gln | missense_variant | 15/24 | 5 | NM_000215.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461872Hom.: 0 Cov.: 39 AF XY: 0.00000413 AC XY: 3AN XY: 727232
GnomAD4 genome ? Cov.: 32
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 | - - |
T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 657 of the JAK3 protein (p.Arg657Gln). This variant is not present in population databases (gnomAD no frequency). 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: 376113). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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