rs150199231

Variant names:

• chr11-36573555-A-G
• rs150199231
• NM_000448.3:c.251A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-36573555-A-G
• chr11-36573555-A-C

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.251A>G variant in RAG1 is a missense variant predicted to cause the substitution of Histidine by Arginine at amino acid 249 (p.His84Arg). The Popmax Filtering allele frequency (95% CI) of the c.251A>G variant in RAG1 is 0.01622 in gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1. Therefore, BA1 is met. Additionally, 19 homozygous adults are reported on 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/CA5949933/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.0050 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 1.57
• Publications: 0 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.251A>G	p.His84Arg	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.251A>G	p.His84Arg	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.251A>G	p.His84Arg	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.251A>G	p.His84Arg	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.251A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.251A>G	p.His84Arg	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 758 AN: 152078 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00115 AC: 288 AN: 251076 AF XY: 0.000744

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000477 AC: 697 AN: 1461892 Hom.: 7 Cov.: 30 AF XY: 0.000389 AC XY: 283 AN XY: 727248

African (AFR) AF: 0.0174 AC: 582 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.00121 AC: 73 AN: 60396

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152196 Hom.: 12 Cov.: 32 AF XY: 0.00508 AC XY: 378 AN XY: 74416

African (AFR) AF: 0.0177 AC: 736 AN: 41518

American (AMR) AF: 0.00111 AC: 17 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67990

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00191 Hom.: 4

Bravo AF: 0.00542

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.44
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.56	T
Polyphen		0.98	D
Vest4		0.22
MVP		0.73
MPC		0.74
ClinPred		0.018	T
GERP RS		3.7
Varity_R		0.027
gMVP		0.30
Mutation Taster		=98/2	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: rs150199231; hg19: chr11-36595105; COSMIC: COSV104408600;