rs199474689
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM2PM5PP3_StrongPP5_Moderate
The NM_000448.3(RAG1):c.2006A>G(p.Glu669Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E669K) 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.2006A>G | p.Glu669Gly | missense_variant | 2/2 | ENST00000299440.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG1 | ENST00000299440.6 | c.2006A>G | p.Glu669Gly | missense_variant | 2/2 | 1 | NM_000448.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
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 | Invitae | May 22, 2023 | 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. This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 669 of the RAG1 protein (p.Glu669Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 11133745, 24144642). ClinVar contains an entry for this variant (Variation ID: 68688). 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. This variant disrupts the p.Glu669 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24144642, 26476733, 28747913, 32655540). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at