rs199474685
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_000448.3(RAG1):c.1331C>T(p.Ala444Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A444A) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
RAG1
NM_000448.3 missense
NM_000448.3 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 7.57
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 12 ACMG points.
PM1
?
In a DNA_binding_region NBD (size 67) in uniprot entity RAG1_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000448.3
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-36574635-C-T is Pathogenic according to our data. Variant chr11-36574635-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68681.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-36574635-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.1331C>T | p.Ala444Val | missense_variant | 2/2 | ENST00000299440.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG1 | ENST00000299440.6 | c.1331C>T | p.Ala444Val | missense_variant | 2/2 | 1 | NM_000448.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250826Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135524
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461890Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8AN XY: 727248
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Recombinase activating gene 1 deficiency Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Nov 14, 2023 | The NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) missense variant occurs in the NBD domain (amino acids 394-460), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199; PM1). The popmax allele frequency is 0.00003266 (1/30614 alleles) in the South Asisan population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). At least 11 patients have been reported with this variant (PMIDs: 26596586, 24290284, 23085344, 17572155, 11133745, 36596882, 29410113), including patient 11 of PMID: 26596586 whom meets diagnostic criteria for SCID with a T-B-NK+ lymphocyte subset profile which is specific to recombinase activating gene 1 deficiency (PP4). Six patients are homozygous for this variant (PMIDs: 24290284, 17572155,11133745; 1pt maximum) and five are compound heterozygous (PMIDs: 26596586, 23085344, 11133745, 36596882, 29410113), harboring this variant as well as c.256_257 (provisionally classified Pathogenic by the SCID VCEP; 1+0.5pt), Val433Met, Lys992Glu, or c.2018_2025del. Total 2.5pt (PM3_Strong). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Ala444Val was 1.4% of wild type +/- 0.2 (PMID: 24290284; PS3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM2_supporting, PP4, PM3_Strong, PS3_Moderate. (VCEP specifications version 1). - |
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" | May 01, 2022 | - - |
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2022 | Variant summary: RAG1 c.1331C>T (p.Ala444Val) results in a non-conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250826 control chromosomes. c.1331C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency/Atypical SCID/Omenn syndrome (example, Villa_2001, Haq_2007, Sharapova_2012, Firtina_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Lee_2014). The most pronounced variant effect results in 1.4% of normal VDJ recombination activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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 | Jan 08, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 444 of the RAG1 protein (p.Ala444Val). This variant is present in population databases (rs199474685, gnomAD 0.003%). This missense change has been observed in individuals with primary immunodeficiency (PMID: 11133745, 23085344, 24290284, 26596586; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68681). 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. 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 | Oct 22, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of helix (P = 0.079);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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