rs1424732031
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_000215.4(JAK3):c.3103delC(p.Leu1035CysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 1,557,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
JAK3
NM_000215.4 frameshift
NM_000215.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.158
Genes affected
JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0806 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-17830211-AG-A is Pathogenic according to our data. Variant chr19-17830211-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523047.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| JAK3 | NM_000215.4 | c.3103delC | p.Leu1035CysfsTer3 | frameshift_variant | Exon 23 of 24 | ENST00000458235.7 | NP_000206.2 | |
| JAK3 | XM_047438786.1 | c.3103delC | p.Leu1035CysfsTer3 | frameshift_variant | Exon 23 of 24 | XP_047294742.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000198 AC: 3AN: 151160Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000213 AC: 3AN: 1405870Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2AN XY: 695618
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GnomAD4 genome 0.0000198 AC: 3AN: 151160Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3AN XY: 73838
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics Facility, Ludwig-Maximilians-Universität München | Dec 28, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 19, 2024 | This sequence change creates a premature translational stop signal (p.Leu1035Cysfs*3) in the JAK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAK3 are known to be pathogenic (PMID: 7481768, 11668621). 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: 523047). For these reasons, this variant has been classified as Pathogenic. - |
Severe combined immunodeficiency disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2025 | Variant summary: JAK3 c.3103delC (p.Leu1035CysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 175540 control chromosomes. To our knowledge, no occurrence of c.3103delC in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 523047). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at