11-36573305-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_ModeratePM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5949886/MONDO:0000572/123
Frequency
Consequence
NM_000448.3 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAG1 | NM_000448.3 | c.1A>G | p.Met1? | start_lost | Exon 2 of 2 | ENST00000299440.6 | NP_000439.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251374Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135870
GnomAD4 exome AF: 0.000153 AC: 223AN: 1461874Hom.: 0 Cov.: 30 AF XY: 0.000155 AC XY: 113AN XY: 727242
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74472
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
PM3, PS4_moderate, PVS1_moderate -
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) -
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
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 gene product 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; internal data). 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
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
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Histiocytic medullary reticulosis Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at