rs1980131

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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]

RAG2 Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• recombinase activating gene 2 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000448.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	NM_000448.3	MANE Select	c.2880A>G	p.Ala960Ala	synonymous	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.2880A>G	p.Ala960Ala	synonymous	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.2880A>G	p.Ala960Ala	synonymous	Exon 4 of 4	NP_001364207.1	P15918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	ENST00000299440.6	TSL:1 MANE Select	c.2880A>G	p.Ala960Ala	synonymous	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.2789+91A>G		intron	N/A	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.2880A>G	p.Ala960Ala	synonymous	Exon 3 of 3	ENSP00000513411.1	P15918-1

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

GnomAD2 exomes AF: 0.0654 AC: 16371 AN: 250426 AF XY: 0.0661

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 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

African (AFR) AF: 0.0776 AC: 2597 AN: 33478

American (AMR) AF: 0.0503 AC: 2248 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 2015 AN: 26136

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39700

South Asian (SAS) AF: 0.0618 AC: 5333 AN: 86258

European-Finnish (FIN) AF: 0.0698 AC: 3727 AN: 53370

Middle Eastern (MID) AF: 0.0999 AC: 576 AN: 5768

European-Non Finnish (NFE) AF: 0.0775 AC: 86223 AN: 1112002

Other (OTH) AF: 0.0779 AC: 4703 AN: 60394

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

African (AFR) AF: 0.0793 AC: 3292 AN: 41528

American (AMR) AF: 0.0742 AC: 1135 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 276 AN: 3472

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5178

South Asian (SAS) AF: 0.0581 AC: 280 AN: 4822

European-Finnish (FIN) AF: 0.0663 AC: 704 AN: 10612

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0795 AC: 5406 AN: 67994

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0761 Hom.: 371

Bravo AF: 0.0754

Asia WGS AF: 0.0390 AC: 138 AN: 3478

EpiCase AF: 0.0864

EpiControl AF: 0.0803

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	not specified (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.49
PhyloP100		-0.43
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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