rs150739647
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000448.3(RAG1):c.2924G>A(p.Arg975Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,964 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. R975W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000448.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.2924G>A | p.Arg975Gln | missense_variant | 2/2 | ENST00000299440.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG1 | ENST00000299440.6 | c.2924G>A | p.Arg975Gln | missense_variant | 2/2 | 1 | NM_000448.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250554Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135518
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461822Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27AN XY: 727210
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2020 | Has been published previously either with a second RAG1 variant or in the homozygous state in patients with RAG1-associated disorders (Villa et al., 2001; Avila et al., 2010; Yu et al., 2016; Meshaal et al, 2019); Published functional studies demonstrate a damaging effect with impaired recombination activity (Wong et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect with impaired recombination activity Lee 2014); This variant is associated with the following publications: (PMID: 28783144, 18768869, 24290284, 11971977, 11133745, 20956421, 30307608, 27484032) - |
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2018 | Variant summary: RAG1 c.2924G>A (p.Arg975Gln) results in a conservative amino acid change located in the C-terminal part of the catalytic core domain (Lee 2014) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276306 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in RAG1 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (4e-05 vs 0.00071), allowing no conclusion about variant significance. c.2924G>A has been described in the literature in compound heterozygosity in individuals affected with Severe Combined Immunodeficiency Syndrome (SCID) or Omenn Syndrome (Villa 2001, Avila 2010, Yu 2016) and it was also reported in an internal sample from a compound heterozygous child affected with Omenn syndrome (OS). The variant was also found in homozygous form in a patient with OS (Meshaal 2015). These data indicate that the variant is very likely to be associated with disease. At least two publications reported experimental evidence evaluating an impact on protein function (Wong 2008, Lee 2014). The most pronounced variant effect resulted in ~60% of normal recombination activity (Lee 2014). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. 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;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 975 of the RAG1 protein (p.Arg975Gln). This variant is present in population databases (rs150739647, gnomAD 0.01%). This missense change has been observed in individual(s) with severe combined immunodeficiency or Omenn syndrome (PMID: 11133745, 27484032, 30307608). ClinVar contains an entry for this variant (Variation ID: 68693). 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 expected to disrupt RAG1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 17476359, 18768869, 24290284). For these reasons, this variant has been classified as Pathogenic. - |
Combined immunodeficiency due to partial RAG1 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at