chr11-36574050-A-G

Variant names:

• chr11-36574050-A-G
• rs3740955
• NM_000448.3:c.746A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The NM_000448.3:c.746A>G variant in RAG1 is a missense variant predicted to cause the substitution of Histidine by Arginine at amino acid 249 (p.His249Arg). The filtering allele frequency (the lower threshold of the 95% CI of 34582/44854) of the c.746A>G variant in RAG1 is 0.7646 for East Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 127763 homozygous adults are reported in gnomAD v.4. BS2_Supporting is Met. In summary, this variant meets the criteria to be classified as Benign for Autosomal Recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950043/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.48 (20429 hom., cov: 32)
  • Exomes 𝑓: 0.36 (107334 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -0.0740
• Publications: 48 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 -9 ACMG points.

• 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.746A>G	p.His249Arg	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.746A>G	p.His249Arg	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.746A>G	p.His249Arg	missense	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.746A>G	p.His249Arg	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.746A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.746A>G	p.His249Arg	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73356 AN: 151960 Hom.: 20372 Cov.: 32

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.451 AC: 113000 AN: 250786 AF XY: 0.433

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.676

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.771

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.364 AC: 532467 AN: 1461832 Hom.: 107334 Cov.: 68 AF XY: 0.365 AC XY: 265399 AN XY: 727208

African (AFR) AF: 0.741 AC: 24793 AN: 33480

American (AMR) AF: 0.662 AC: 29621 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9493 AN: 26136

East Asian (EAS) AF: 0.772 AC: 30640 AN: 39696

South Asian (SAS) AF: 0.461 AC: 39789 AN: 86256

European-Finnish (FIN) AF: 0.295 AC: 15731 AN: 53404

Middle Eastern (MID) AF: 0.414 AC: 2390 AN: 5768

European-Non Finnish (NFE) AF: 0.320 AC: 355930 AN: 1111980

Other (OTH) AF: 0.399 AC: 24080 AN: 60392

GnomAD4 genome AF: 0.483 AC: 73476 AN: 152078 Hom.: 20429 Cov.: 32 AF XY: 0.487 AC XY: 36195 AN XY: 74332

African (AFR) AF: 0.730 AC: 30294 AN: 41472

American (AMR) AF: 0.567 AC: 8661 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1289 AN: 3470

East Asian (EAS) AF: 0.764 AC: 3942 AN: 5158

South Asian (SAS) AF: 0.485 AC: 2336 AN: 4814

European-Finnish (FIN) AF: 0.288 AC: 3048 AN: 10580

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22338 AN: 67978

Other (OTH) AF: 0.473 AC: 999 AN: 2112

Alfa AF: 0.387 Hom.: 46203

Bravo AF: 0.517

TwinsUK AF: 0.321 AC: 1189

ALSPAC AF: 0.317 AC: 1221

ESP6500AA AF: 0.727 AC: 3200

ESP6500EA AF: 0.336 AC: 2888

ExAC AF: 0.447 AC: 54243

Asia WGS AF: 0.639 AC: 2220 AN: 3478

EpiCase AF: 0.339

EpiControl AF: 0.332

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2)
-	-	1	Combined immunodeficiency with skin granulomas (1)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	Immunodeficiency 104 (1)
-	-	1	Recombinase activating gene 1 deficiency (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
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.26
DANN	Benign	0.51
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.081	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.29	N
PhyloP100		-0.074
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.026
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.23
ClinPred		0.0082	T
GERP RS		-2.0
Varity_R		0.026
gMVP		0.32
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: rs3740955; hg19: chr11-36595600; COSMIC: COSV55024167; COSMIC: COSV55024167;