rs121918571
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The ENST00000299440.6(RAG1):c.983G>A(p.Cys328Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,060 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
RAG1
ENST00000299440.6 missense
ENST00000299440.6 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
RAG1 (HGNC:9831): (recombination activating 1) The protein encoded by this gene is involved in activation of immunoglobulin V-D-J recombination. The encoded protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. Defects in this gene can be the cause of several diseases. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant 11-36574287-G-A is Pathogenic according to our data. Variant chr11-36574287-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-36574287-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.983G>A | p.Cys328Tyr | 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.983G>A | p.Cys328Tyr | missense_variant | 2/2 | 1 | NM_000448.3 | ENSP00000299440 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461894Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5AN XY: 727248
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74324
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Histiocytic medullary reticulosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 2007 | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 328 of the RAG1 protein (p.Cys328Tyr). This variant is present in population databases (rs121918571, gnomAD no frequency). This missense change has been observed in individual(s) with Omenn syndrome and with clinical features of severe combined immunodeficiency (PMID: 11133745, 17572155; Invitae). 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: 13160). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 18056378, 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 | Sep 04, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at