chr11-36573305-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP5_Strong
The NM_000448.3(RAG1):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000145 in 1,614,160 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 Uncertain significance (★★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
RAG1
NM_000448.3 start_lost
NM_000448.3 start_lost
Scores
6
7
3
Clinical Significance
Conservation
PhyloP100: 4.15
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.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-36573305-A-G is Pathogenic according to our data. Variant chr11-36573305-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 304491.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.1A>G | p.Met1? | start_lost | 2/2 | ENST00000299440.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAG1 | ENST00000299440.6 | c.1A>G | p.Met1? | start_lost | 2/2 | 1 | NM_000448.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251374Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135870
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GnomAD4 exome AF: 0.000153 AC: 223AN: 1461874Hom.: 0 Cov.: 30 AF XY: 0.000155 AC XY: 113AN XY: 727242
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GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74472
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2020 | Functional studies indicate that this variant may have a partial effect on mRNA expression and protein level (Geier et al., 2015); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589898, 33193364, 26186701, 31980526) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 26, 2021 | PM3, PS4_moderate, PVS1_moderate - |
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 | Dec 21, 2023 | This sequence change affects the initiator methionine of the RAG1 mRNA. The next in-frame methionine is located at codon 183. This variant is present in population databases (rs200575481, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with RAG1-related disease (PMID: 26186701). ClinVar contains an entry for this variant (Variation ID: 304491). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects RAG1 function (PMID: 26186701). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Cys176Phe) have been determined to be pathogenic (PMID: 26457731, 28769923; Invitae). 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. - |
Recombinase activating gene 1 deficiency Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Oct 10, 2023 | The NM_000448.3:c.1A>G (p.Met1Val) variant in RAG1 is an initiation codon variant that is not expected to result in nonsense-mediated mRNA decay but may cause a truncated protein by using an alternative start codon (Met183). There is one frameshift variant (p.K86VfsX33) that occurs upstream of codon 183, which causes the production of an N-terminally truncated RAG1 with low recombination activity and altered cellular localization (PMIDs 24290284, 11121059, 27301863) (PVS1_Moderate). The gnomAD 2.1.1 Popmax filtering allele frequency of this variant is 0.0001017, which is lower than the SCID VCEP threshold for PM2 (0.000102), and no homozygous individual has been observed in the gnomAD. Therefore it meets this criterion (PM2_Supporting). The variant has been detected in at least four individuals diagnosed with primary immunodeficiency. Patient A, reported by PMID 26186701, was heterozygous for this variant and a p.R737H variant (not curated by the SCID-VCEP), 0 pt. The other three individuals were reported in ClinVar entries without the information of the second allele, and in all three entries, the variant was classified as Uncertain Significance (Illumina Laboratory Services, SCV000371654.2; Illumina Laboratory Services, SCV000371655.2; Invitae, SCV001230493.3). The reported patient information is not sufficient to meet PM3 or PP4 criteria. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Moderate, PM2_Supporting (SCID VCEP specifications version 1.0). - |
Severe combined immunodeficiency disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Histiocytic medullary reticulosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
ClinPred
D
GERP RS
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gMVP
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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