rs34841221

Positions:

chr11-36573881-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 c.577G>A (NM_000448.3) variant in RAG1 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 193 (p.Glu193Lys).The filtering allele frequency (the lower threshold of the 95% CI of 772/30614) of the c.577G>A variant in RAG1 is 0.02374 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). 12 adult homozygous reported on GnomAD v2.1.1, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950009/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 43 hom. )

Consequence

RAG1
NM_000448.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 4.08

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.577G>A	p.Glu193Lys	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.577G>A	p.Glu193Lys	missense_variant	2/2	1	NM_000448.3	ENSP00000299440.5		P15918-1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00385

AC:

965

AN:

250940

Hom.:

AF XY:

0.00467

AC XY:

633

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0252

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00196

AC:

2866

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

1904

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0239

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000339

Gnomad4 OTH exome

AF:

0.00315

GnomAD4 genome

AF:

0.00204

AC:

310

AN:

152250

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0234

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000700

Hom.:

Bravo

AF:

0.00143

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00412

AC:

500

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2018	Variant summary: RAG1 c.577G>A (p.Glu193Lys) results in a conservative amino acid change located in the RAG1 importin-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 276652 control chromosomes, predominantly at a frequency of 0.025 within the South Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 35.36 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG1 causing Severe Combined Immunodeficiency Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.577G>A in individuals affected with Severe Combined Immunodeficiency Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

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.577G>A (NM_000448.3) variant in RAG1 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 193 (p.Glu193Lys). The filtering allele frequency (the lower threshold of the 95% CI of 772/30614) of the c.577G>A variant in RAG1 is 0.02374 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). 12 adult homozygous reported on GnomAD v2.1.1, BS2_Supporting is Met. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (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

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

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

0.089

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

2.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.059

Polyphen

0.025

Vest4

0.20

MVP

0.79

MPC

0.74

ClinPred

0.063

GERP RS

5.0

Varity_R

0.14

gMVP

0.82

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