rs121918568
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The ENST00000299440.6(RAG1):c.940C>T(p.Arg314Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,888 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314Q) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000299440.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.940C>T | p.Arg314Trp | missense_variant | 2/2 | ENST00000299440.6 | NP_000439.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAG1 | ENST00000299440.6 | c.940C>T | p.Arg314Trp | missense_variant | 2/2 | 1 | NM_000448.3 | ENSP00000299440 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Combined immunodeficiency with skin granulomas Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 08, 2008 | - - |
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 314 of the RAG1 protein (p.Arg314Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with atypical severe combined immunodeficiency and/or combined immunodeficiency (PMID: 18463379, 32445296). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13156). 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 RAG1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 18463379, 24290284). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Combined immunodeficiency due to partial RAG1 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 22, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at