rs1980131

Variant names:

• chr11-36576184-A-G
• rs1980131
• NM_000448.3:c.2880A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000448.3(RAG1):​c.2880A>G​(p.Ala960Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,614,052 control chromosomes in the GnomAD database, including 4,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (470 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4130 hom.)
• Consequence: RAG1 NM_000448.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.427

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]

RAG2 (HGNC:9832): (recombination activating 2) This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-36576184-A-G is Benign according to our data. Variant chr11-36576184-A-G is described in ClinVar as [Benign]. Clinvar id is 256190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-36576184-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.427 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_000448.3	c.2880A>G	p.Ala960Ala	synonymous_variant	Exon 2 of 2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6	c.2880A>G	p.Ala960Ala	synonymous_variant	Exon 2 of 2	1	NM_000448.3	ENSP00000299440.5

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11415 AN: 152104 Hom.: 471 Cov.: 32

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0576

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0871

GnomAD3 exomes AF: 0.0654 AC: 16371 AN: 250426 Hom.: 587 AF XY: 0.0661 AC XY: 8965 AN XY: 135530

Gnomad AFR exome AF: 0.0767

Gnomad AMR exome AF: 0.0489

Gnomad ASJ exome AF: 0.0794

Gnomad EAS exome AF: 0.00136

Gnomad SAS exome AF: 0.0604

Gnomad FIN exome AF: 0.0672

Gnomad NFE exome AF: 0.0786

Gnomad OTH exome AF: 0.0716

GnomAD4 exome AF: 0.0735 AC: 107471 AN: 1461830 Hom.: 4130 Cov.: 34 AF XY: 0.0738 AC XY: 53644 AN XY: 727220

Gnomad4 AFR exome AF: 0.0776

Gnomad4 AMR exome AF: 0.0503

Gnomad4 ASJ exome AF: 0.0771

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.0618

Gnomad4 FIN exome AF: 0.0698

Gnomad4 NFE exome AF: 0.0775

Gnomad4 OTH exome AF: 0.0779

GnomAD4 genome AF: 0.0751 AC: 11428 AN: 152222 Hom.: 470 Cov.: 32 AF XY: 0.0746 AC XY: 5549 AN XY: 74426

Gnomad4 AFR AF: 0.0793

Gnomad4 AMR AF: 0.0742

Gnomad4 ASJ AF: 0.0795

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0581

Gnomad4 FIN AF: 0.0663

Gnomad4 NFE AF: 0.0795

Gnomad4 OTH AF: 0.0852

Alfa AF: 0.0776 Hom.: 284

Bravo AF: 0.0754

Asia WGS AF: 0.0390 AC: 138 AN: 3478

EpiCase AF: 0.0864

EpiControl AF: 0.0803

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.49

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: rs1980131; hg19: chr11-36597734; COSMIC: COSV55026991;