11-36574050-A-G

Position:

chr11-36574050-A-G

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.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

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -0.0740

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:

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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.746A>G	p.His249Arg	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.746A>G	p.His249Arg	missense_variant	2/2	1	NM_000448.3	ENSP00000299440.5		P15918-1

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73356

AN:

151960

Hom.:

20372

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.451

AC:

113000

AN:

250786

Hom.:

29355

AF XY:

0.433

AC XY:

58702

AN XY:

135514

show subpopulations

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 SAS exome

AF:

0.467

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.:

AF XY:

0.365

AC XY:

265399

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.741

Gnomad4 AMR exome

AF:

0.662

Gnomad4 ASJ exome

AF:

0.363

Gnomad4 EAS exome

AF:

0.772

Gnomad4 SAS exome

AF:

0.461

Gnomad4 FIN exome

AF:

0.295

Gnomad4 NFE exome

AF:

0.320

Gnomad4 OTH exome

AF:

0.399

GnomAD4 genome

AF:

0.483

AC:

73476

AN:

152078

Hom.:

20429

Cov.:

AF XY:

0.487

AC XY:

36195

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.730

Gnomad4 AMR

AF:

0.567

Gnomad4 ASJ

AF:

0.371

Gnomad4 EAS

AF:

0.764

Gnomad4 SAS

AF:

0.485

Gnomad4 FIN

AF:

0.288

Gnomad4 NFE

AF:

0.329

Gnomad4 OTH

AF:

0.473

Alfa

AF:

0.368

Hom.:

27976

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

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 76. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - papers in HGMD do not provide evidence of disease association -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Combined immunodeficiency with skin granulomas

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

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.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). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Histiocytic medullary reticulosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

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

Feb 01, 2024

- -

Immunodeficiency 104

Benign:1

Benign, criteria provided, single submitter

clinical testing

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

The variant is predicted to be benign by PolyPhen2. The amino acid change p.His249Arg in RAG1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.26

DANN

Benign

0.51

DEOGEN2

Benign

0.11

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.081

MetaRNN

Benign

9.0e-7

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.29

PrimateAI

Benign

0.21

PROVEAN

Benign

0.50

REVEL

Benign

0.026

Sift

Benign

0.21

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.015

MPC

0.23

ClinPred

0.0082

GERP RS

-2.0

Varity_R

0.026

gMVP

0.32

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