rs878853031

chr11-36574078-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000448.3(RAG1):c.775del(p.Ser259AlafsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,858 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. S259S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RAG1 NM_000448.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.960

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 140 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-36574078-CA-C is Pathogenic according to our data. Variant chr11-36574078-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 235411.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG1	NM_000448.3	c.775del	p.Ser259AlafsTer5	frameshift_variant	2/2	ENST00000299440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG1	ENST00000299440.6	c.775del	p.Ser259AlafsTer5	frameshift_variant	2/2	1	NM_000448.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461858 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2020	Variant summary: RAG1 c.775delA (p.Ser259AlafsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250934 control chromosomes (gnomAD). c.775delA has been reported in the literature in individuals affected with Omenn Syndrome (examples- Santagata_2000, Sobacchi_2006, Dobbs_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in reduced levels of V(D)J recombination and reduced nuclear localization of the protein (Santagata_2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 19, 2000	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2018	The c.775delA variant has been reported previously in association with Omenn syndrome (Santagata et al., 2000; Sobacchi et al., 2006). The deletion causes a frameshift starting with codon Serine 259, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Ser259AlafsX5. Functional studies have shown this variant results in decreased activity of the RAG1 protein and interferes with proper protein localization (Santagata et al., 2000). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2016	- -

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 nonsense variant NM_000448.3(RAG1):c.775del (p.Ser259AlafsTer5) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense mediated decay but does truncate 75% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). This variant is absent from gnomADv2.1.1 (PM2_Supporting). It has been reported homozygous in one patient with Omenn syndrome (PM3_supporting) with insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). 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: PVS1, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1). -

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

Feb 15, 2023

This sequence change creates a premature translational stop signal (p.Ser259Alafs*5) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 785 amino acid(s) of the RAG1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Omenn syndrome (PMID: 11121059, 16960852, 28769923). This variant is also known as g.887delA. ClinVar contains an entry for this variant (Variation ID: 235411). 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 this premature translational stop signal affects RAG1 function (PMID: 11121059). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.W959*) have been determined to be pathogenic (PMID: 11133745, 24290284, 24406074). 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. -

Combined immunodeficiency due to partial RAG1 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853031; hg19: chr11-36595628;