11-36574650-G-A

Position:

chr11-36574650-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2_SupportingBA1

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

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:8

Conservation

PhyloP100: 4.40

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
RAG1	NM_000448.3 linkuse as main transcript	c.1346G>A	p.Arg449Lys	missense_variant	2/2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6 linkuse as main transcript	c.1346G>A	p.Arg449Lys	missense_variant	2/2	1	NM_000448.3	ENSP00000299440	P1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1554

AN:

152224

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00975

AC:

2446

AN:

250856

Hom.:

AF XY:

0.00963

AC XY:

1306

AN XY:

135560

show subpopulations

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 SAS exome

AF:

0.00118

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.:

AF XY:

0.0149

AC XY:

10859

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00123

Gnomad4 FIN exome

AF:

0.0144

Gnomad4 NFE exome

AF:

0.0186

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.0102

AC:

1553

AN:

152342

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

707

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.00771

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0107

Gnomad4 NFE

AF:

0.0167

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0100

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.0104

AC:

1266

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0125

EpiControl

AF:

0.0145

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24290284, 21228398, 16960852, 27609655, 33046446) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RAG1: PM5, BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2019	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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Jan 23, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.31

Sift

Benign

0.048

Sift4G

Benign

0.13

Polyphen

0.95

Vest4

0.091

MPC

0.62

ClinPred

0.052

GERP RS

3.8

Varity_R

0.10

gMVP

0.49

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over