rs4151031

Variant names:

• chr11-36574650-G-A
• rs4151031
• NM_000448.3:c.1346G>A

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.1346G>A variant in RAG1 is a missense variant predicted to cause the substitution of Arginine by Lysine at amino acid 449 (p.Arg449Lys). The filtering allele frequency (the lower threshold of the 95% CI of 21803/1180030) of the c.1346G>A variant in RAG1 is 0.01837 for European (non-Finnish) 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, 207 homozygous adults are reported on gnomAD v.4 (BS2_Supporting). 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/CA5950130/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 33)
  • Exomes 𝑓: 0.015 (190 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 4.40
• Publications: 16 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_000448.3	c.1346G>A	p.Arg449Lys	missense_variant	Exon 2 of 2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6	c.1346G>A	p.Arg449Lys	missense_variant	Exon 2 of 2	1	NM_000448.3	ENSP00000299440.5

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152224 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00975 AC: 2446 AN: 250856 AF XY: 0.00963

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.0154 AC: 22480 AN: 1461880 Hom.: 190 Cov.: 36 AF XY: 0.0149 AC XY: 10859 AN XY: 727242

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00264 AC: 118 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00123 AC: 106 AN: 86258

European-Finnish (FIN) AF: 0.0144 AC: 769 AN: 53412

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0186 AC: 20668 AN: 1112008

Other (OTH) AF: 0.0113 AC: 680 AN: 60396

GnomAD4 genome AF: 0.0102 AC: 1553 AN: 152342 Hom.: 17 Cov.: 33 AF XY: 0.00949 AC XY: 707 AN XY: 74496

African (AFR) AF: 0.00286 AC: 119 AN: 41582

American (AMR) AF: 0.00771 AC: 118 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0167 AC: 1135 AN: 68022

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.0138 Hom.: 80

Bravo AF: 0.0100

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.0104 AC: 1266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0145

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Oct 25, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24290284, 21228398, 16960852, 27609655, 33046446) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAG1: PM5, BS1, BS2 -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAG1 c.1346G>A (p.Arg449Lys) results in a conservative amino acid change located in the RAG nonamer-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0098 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the Non-Finnish European subpopulation in the gnomAD database, including 20 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24-folds over the estimated maximal expected allele frequency for a pathogenic variant in RAG1 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1346G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Haq_2007, Sobacchi_2006, Lee_2014, Kumanovics_2017). These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome. Co-occurrences with RAG1 pathogenic variants in cis have been reported (R404Q and R410Q), providing supporting evidence for a benign role. Functional study, Lee_2014, found the variant to have comparable levels to wild type for recombination activity. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Histiocytic medullary reticulosis Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Recombinase activating gene 1 deficiency Benign:1

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000448.3:c.1346G>A variant in RAG1 is a missense variant predicted to cause the substitution of Arginine by Lysine at amino acid 449 (p.Arg449Lys). The filtering allele frequency (the lower threshold of the 95% CI of 21803/1180030) of the c.1346G>A variant in RAG1 is 0.01837 for European (non-Finnish) 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, 207 homozygous adults are reported on gnomAD v.4 (BS2_Supporting). 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). -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.048	D
Sift4G	Benign	0.13	T
Polyphen		0.95	P
Vest4		0.091
MPC		0.62
ClinPred		0.052	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.49
Mutation Taster		=80/20	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: rs4151031; hg19: chr11-36596200; COSMIC: COSV104408609;