rs34357808

Variant names:

• chr11-36573493-A-G
• rs34357808
• NM_000448.3:c.189A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-36573493-A-G
• chr11-36573493-A-T
• chr11-36573493-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000448.3(RAG1):​c.189A>G​(p.Pro63Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,614,232 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P63P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (40 hom.)
• Consequence: RAG1 NM_000448.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.143
• Publications: 2 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]

RAG1 Gene-Disease associations (from GenCC):

• immunodeficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• recombinase activating gene 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-36573493-A-G is Benign according to our data. Variant chr11-36573493-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.143 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2013/152346) while in subpopulation AFR AF = 0.0446 (1856/41570). AF 95% confidence interval is 0.043. There are 50 homozygotes in GnomAd4. There are 1007 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

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.189A>G	p.Pro63Pro	synonymous	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.189A>G	p.Pro63Pro	synonymous	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.189A>G	p.Pro63Pro	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.189A>G	p.Pro63Pro	synonymous	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.189A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.189A>G	p.Pro63Pro	synonymous	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2014 AN: 152228 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00380 AC: 953 AN: 250928 AF XY: 0.00297

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000538

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00153 AC: 2233 AN: 1461886 Hom.: 40 Cov.: 30 AF XY: 0.00137 AC XY: 994 AN XY: 727246

African (AFR) AF: 0.0431 AC: 1443 AN: 33480

American (AMR) AF: 0.00394 AC: 176 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000279 AC: 310 AN: 1112012

Other (OTH) AF: 0.00344 AC: 208 AN: 60392

GnomAD4 genome AF: 0.0132 AC: 2013 AN: 152346 Hom.: 50 Cov.: 32 AF XY: 0.0135 AC XY: 1007 AN XY: 74502

African (AFR) AF: 0.0446 AC: 1856 AN: 41570

American (AMR) AF: 0.00588 AC: 90 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68040

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00657 Hom.: 13

Bravo AF: 0.0146

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	RAG1-related disorder (1)
-	-	1	Severe combined immunodeficiency disease (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	-0.85
CADD	Benign	5.4
DANN	Benign	0.73
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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: rs34357808; hg19: chr11-36595043; COSMIC: COSV104408579;