11-36575763-A-G

Position:

chr11-36575763-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.2459A>G variant in RAG1 is a missense variant predicted to cause the substitution of Lysine by Arginine at amino acid 820 (p.Lys820Arg). The filtering allele frequency (the lower threshold of the 95% CI of 26338/44862) of the c.2459A>G variant in RAG1 is 0.5818 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, 22786 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/CA5950267/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.14 ( 2323 hom., cov: 33)

Exomes 𝑓: 0.14 ( 20463 hom. )

Consequence

RAG1
NM_000448.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: 2.86

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:

RAG2 (HGNC:):

RAG2 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.2459A>G	p.Lys820Arg	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.2459A>G	p.Lys820Arg	missense_variant	2/2	1	NM_000448.3	ENSP00000299440.5		P15918-1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21427

AN:

152140

Hom.:

2319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0997

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.235

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.579

Gnomad SAS

AF:

0.279

Gnomad FIN

AF:

0.0865

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.149

GnomAD3 exomes

AF:

0.195

AC:

48854

AN:

250564

Hom.:

7531

AF XY:

0.190

AC XY:

25783

AN XY:

135432

show subpopulations

Gnomad AFR exome

AF:

0.0982

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.166

Gnomad EAS exome

AF:

0.590

Gnomad SAS exome

AF:

0.261

Gnomad FIN exome

AF:

0.0839

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.170

GnomAD4 exome

AF:

0.136

AC:

198634

AN:

1461858

Hom.:

20463

Cov.:

AF XY:

0.139

AC XY:

101107

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0966

Gnomad4 AMR exome

AF:

0.334

Gnomad4 ASJ exome

AF:

0.163

Gnomad4 EAS exome

AF:

0.588

Gnomad4 SAS exome

AF:

0.252

Gnomad4 FIN exome

AF:

0.0879

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.158

GnomAD4 genome

AF:

0.141

AC:

21442

AN:

152260

Hom.:

2323

Cov.:

AF XY:

0.147

AC XY:

10975

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0995

Gnomad4 AMR

AF:

0.236

Gnomad4 ASJ

AF:

0.163

Gnomad4 EAS

AF:

0.579

Gnomad4 SAS

AF:

0.278

Gnomad4 FIN

AF:

0.0865

Gnomad4 NFE

AF:

0.107

Gnomad4 OTH

AF:

0.153

Alfa

AF:

0.120

Hom.:

3507

Bravo

AF:

0.152

TwinsUK

AF:

0.112

AC:

414

ALSPAC

AF:

0.104

AC:

399

ESP6500AA

AF:

0.108

AC:

474

ESP6500EA

AF:

0.114

AC:

981

ExAC

AF:

0.186

AC:

22633

Asia WGS

AF:

0.371

AC:

1287

AN:

3478

EpiCase

AF:

0.111

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:13

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 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Histiocytic medullary reticulosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16857995, 24290284, 22424479, 21625022) -

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.2459A>G variant in RAG1 is a missense variant predicted to cause the substitution of Lysine by Arginine at amino acid 820 (p.Lys820Arg). The filtering allele frequency (the lower threshold of the 95% CI of 26338/44862) of the c.2459A>G variant in RAG1 is 0.5818 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, 22786 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). -

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 and the residue is conserved across species. The amino acid change p.Lys820Arg in RAG1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.000045

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Uncertain

0.0010

Sift4G

Benign

0.099

Polyphen

0.0010

Vest4

0.019

MPC

0.15

ClinPred

0.034

GERP RS

2.6

Varity_R

0.14

gMVP

0.46

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