chr11-36573607-G-A

Variant names:

• chr11-36573607-G-A
• rs4151025
• NM_000448.3:c.303G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BS2_Supporting BA1

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:
  • Genomes: 𝑓 0.016 (37 hom., cov: 32)
  • Exomes 𝑓: 0.022 (440 hom.)
• Consequence: RAG1 NM_000448.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -0.753
• 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]

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: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.303G>A	p.Ala101Ala	synonymous	Exon 2 of 2	NP_000439.2
	RAG1	NM_001377277.1		c.303G>A	p.Ala101Ala	synonymous	Exon 5 of 5	NP_001364206.1
	RAG1	NM_001377278.1		c.303G>A	p.Ala101Ala	synonymous	Exon 4 of 4	NP_001364207.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	ENST00000299440.6	TSL:1 MANE Select	c.303G>A	p.Ala101Ala	synonymous	Exon 2 of 2	ENSP00000299440.5
	RAG1	ENST00000534663.1	TSL:1	n.303G>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1
	RAG1	ENST00000697713.1		c.303G>A	p.Ala101Ala	synonymous	Exon 3 of 3	ENSP00000513411.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2456 AN: 152130 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00406

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0169 AC: 4249 AN: 251226 AF XY: 0.0179

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00850

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00998

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0222 AC: 32435 AN: 1461888 Hom.: 440 Cov.: 31 AF XY: 0.0225 AC XY: 16332 AN XY: 727248

African (AFR) AF: 0.00317 AC: 106 AN: 33480

American (AMR) AF: 0.00908 AC: 406 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 270 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0266 AC: 2298 AN: 86258

European-Finnish (FIN) AF: 0.0110 AC: 587 AN: 53420

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5768

European-Non Finnish (NFE) AF: 0.0247 AC: 27437 AN: 1112006

Other (OTH) AF: 0.0201 AC: 1213 AN: 60396

GnomAD4 genome AF: 0.0161 AC: 2451 AN: 152248 Hom.: 37 Cov.: 32 AF XY: 0.0155 AC XY: 1153 AN XY: 74438

African (AFR) AF: 0.00404 AC: 168 AN: 41538

American (AMR) AF: 0.0131 AC: 201 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0262 AC: 126 AN: 4806

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0257 AC: 1748 AN: 68024

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.0199 Hom.: 100

Bravo AF: 0.0150

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0282

EpiControl AF: 0.0277

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	Recombinase activating gene 1 deficiency (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	-0.94
CADD	Benign	0.67
DANN	Benign	0.84
PhyloP100		-0.75
Mutation Taster		=100/0	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: rs4151025; hg19: chr11-36595157; COSMIC: COSV104408578; COSMIC: COSV104408578;