rs749481781
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000215.4(JAK3):c.2680+3G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000215.4 splice_donor_region, intron
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.2680+3G>C | splice_donor_region_variant, intron_variant | ENST00000458235.7 | |||
JAK3 | XM_047438786.1 | c.2680+3G>C | splice_donor_region_variant, intron_variant | ||||
JAK3 | XR_007066796.1 | n.2733G>C | non_coding_transcript_exon_variant | 19/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAK3 | ENST00000458235.7 | c.2680+3G>C | splice_donor_region_variant, intron_variant | 5 | NM_000215.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461858Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727232
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
T-B+ severe combined immunodeficiency due to JAK3 deficiency Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 06, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change falls in intron 19 of the JAK3 gene. It does not directly change the encoded amino acid sequence of the JAK3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs749481781, gnomAD 0.003%). This variant has been observed in individual(s) with severe combined immunodeficiency and/or partial JAK3 deficiency (PMID: 11668621, 11781709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as intron 18 G2775(+3)C or IVS18+3G>C. ClinVar contains an entry for this variant (Variation ID: 328503). Studies have shown that this variant alters JAK3 gene expression (PMID: 11781709). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in retention of 87 nucleotides from intron 19 and introduces a premature termination codon (PMID: 11781709). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The JAK3 c.2680+3G>C variant has been reported in three studies, all of which describe the same two siblings with severe combined immune deficiency who carry the variant in a compound heterozygous state (Mella et al. 2001; Notarangelo et al. 2001; Frucht et al. 2001). One sibling presented with a very severe phenotype and the other with a mild, nearly normal phenotype, but both siblings were found to carry the c.2680+3G>C variant along with an initiator codon variant. The c.2680+3G>C variant was also found in a heterozygous state in their unaffected mother (Frucht et al. 2001). The variant was absent from 100 healthy control chromosomes and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Analysis of cDNA from the sibling with the mild phenotype showed that the c.2680+3G>C variant results in both normally spliced exon 18 and a product containing an intronic sequence that leads to a premature termination of the protein (Frucht et al. 2001). Based on the evidence, the c.2680+3G>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for severe combined immune deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at