Variant chr11-36573607-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The c.303G>A (p.Ala101=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 799/30614) of the c.303G>A variant in RAG1 is 0.02460 for South Asian chromosomes by gnomAD v2.1.1 which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and therefore meets this criterion (BA1). Additionally, 76 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as a Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BA1, BS2_Supporting, and BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA293046/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.016 ( 37 hom., cov: 32)

Exomes 𝑓: 0.022 ( 440 hom. )

Consequence

RAG1
NM_000448.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: -0.753

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 -10 ACMG points.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

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.303G>A	p.Ala101=	synonymous_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.303G>A	p.Ala101=	synonymous_variant	2/2	1	NM_000448.3	ENSP00000299440	P1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2456

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00406

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0266

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.0169

AC:

4249

AN:

251226

Hom.:

AF XY:

0.0179

AC XY:

2433

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00850

Gnomad ASJ exome

AF:

0.00933

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0261

Gnomad FIN exome

AF:

0.00998

Gnomad NFE exome

AF:

0.0236

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0222

AC:

32435

AN:

1461888

Hom.:

440

Cov.:

AF XY:

0.0225

AC XY:

16332

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00317

Gnomad4 AMR exome

AF:

0.00908

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0266

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.0247

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0161

AC:

2451

AN:

152248

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1153

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00404

Gnomad4 AMR

AF:

0.0131

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0262

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.0257

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0193

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0282

EpiControl

AF:

0.0277

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Recombinase activating gene 1 deficiency

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Nov 14, 2023

The c.303G>A (p.Ala101=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The filtering allele frequency (the lower threshold of the 95% CI of 799/30614) of the c.303G>A variant in RAG1 is 0.02460 for South Asian chromosomes by gnomAD v2.1.1 which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and therefore meets this criterion (BA1). Additionally, 76 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as a Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BA1, BS2_Supporting, and BP7. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Histiocytic medullary reticulosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.67

DANN

Benign

0.84

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