11-36573607-G-A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BS2_SupportingBA1
This summary comes from the ClinGen Evidence Repository: The c.303G>A (p.Ala101=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 799/30614) of the c.303G>A variant in RAG1 is 0.02460 for South Asian chromosomes by gnomAD v2.1.1 which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and therefore meets this criterion (BA1). Additionally, 76 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as a Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BA1, BS2_Supporting, and BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA293046/MONDO:0000572/123
Frequency
Consequence
NM_000448.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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RAG1 | NM_000448.3 | c.303G>A | p.Ala101Ala | synonymous_variant | Exon 2 of 2 | ENST00000299440.6 | NP_000439.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0161 AC: 2456AN: 152130Hom.: 37 Cov.: 32
GnomAD3 exomes AF: 0.0169 AC: 4249AN: 251226Hom.: 67 AF XY: 0.0179 AC XY: 2433AN XY: 135764
GnomAD4 exome AF: 0.0222 AC: 32435AN: 1461888Hom.: 440 Cov.: 31 AF XY: 0.0225 AC XY: 16332AN XY: 727248
GnomAD4 genome AF: 0.0161 AC: 2451AN: 152248Hom.: 37 Cov.: 32 AF XY: 0.0155 AC XY: 1153AN XY: 74438
ClinVar
Submissions by phenotype
not specified Benign:2
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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not provided Benign:2
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Recombinase activating gene 1 deficiency Benign:1
The c.303G>A (p.Ala101=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The filtering allele frequency (the lower threshold of the 95% CI of 799/30614) of the c.303G>A variant in RAG1 is 0.02460 for South Asian chromosomes by gnomAD v2.1.1 which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and therefore meets this criterion (BA1). Additionally, 76 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as a Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BA1, BS2_Supporting, and BP7. -
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Histiocytic medullary reticulosis Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at