11-36573626-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000448.3(RAG1):c.322C>T(p.Arg108*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,022 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 (★★).
Frequency
Consequence
NM_000448.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.322C>T | p.Arg108* | stop_gained | Exon 2 of 2 | ENST00000299440.6 | NP_000439.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251282Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135808
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727242
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74294
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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Published functional studies demonstrate a damaging effect: reduced VDJ recombination activity (PMID: 24290284); Nonsense variant predicted to result in protein truncation, as the last 936 amino acids are lost, and other loss-of-function variants have been reported; This variant is associated with the following publications: (PMID: 21664875, 24290284, 28783691, 31589898, 31589614, 32888943, 35753512, 36790564, 36279417, 27825771, 30290665) -
Severe combined immunodeficiency disease Pathogenic:1
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Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg108*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 936 amino acid(s) of the RAG1 protein. This variant is present in population databases (rs193922464, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 21664875, 24290284, 30290665). ClinVar contains an entry for this variant (Variation ID: 36714). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RAG1 function (PMID: 24290284). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Trp959*) have been determined to be pathogenic (PMID: 11133745, 24290284, 24406074). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
RAG1-related disorder Pathogenic:1
The RAG1 c.322C>T (p.Arg108Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg108Ter variant has been reported in at least three studies in which it is found in a total of four individuals including in one in a homozygous state and three in a compound heterozygous state (Lee et al. 2014; Bai et al. 2016; Sharapova et al. 2016; Chi et al. 2018). Two of these individuals were described as having combined immune deficiency with one specifically diagnosed with Omenn syndrome. Control data are not available for the p.Arg108Ter variant which is reported at a frequency of 0.000159 in the East Asian population of the Genome Aggregation Database. Functional studies in cultured cells by Lee et al. (2014) demonstrated that the variant results in significantly reduced enzyme activity compared to wild type. Based on the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Arg108Ter variant is classified as pathogenic for RAG1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Combined immunodeficiency due to partial RAG1 deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at