rs199474684
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000448.3(RAG1):c.1229G>A(p.Arg410Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,120 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 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.1229G>A | p.Arg410Gln | missense_variant | Exon 2 of 2 | ENST00000299440.6 | NP_000439.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250774Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135678
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461872Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9AN XY: 727236
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
Histiocytic medullary reticulosis Pathogenic:1
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RAG1 -related disorder (PMID: 11133745). A different missense change at the same codon (p.Arg410Trp) has been reported to be associated with RAG1 -related disorder (ClinVar ID: VCV000859249/ PMID: 24290284). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
This missense change has been observed in individuals with severe combined immunodeficiency, Omenn syndrome (PMID: 11133745, 24406074, 27609655, 31031743). This variant is present in population databases (rs199474684, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 410 of the RAG1 protein (p.Arg410Gln). ClinVar contains an entry for this variant (Variation ID: 68678). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg410 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24144642, 24290284, 24406074, 28769923). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). 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. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at