rs1424732031
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
Consequence
NM_000215.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
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 AF: 0.0000198 AC: 3AN: 151160Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000213 AC: 3AN: 1405870Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2AN XY: 695618
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151160Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3AN XY: 73838
ClinVar
Submissions by phenotype
T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:2
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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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at