rs199474676

Positions:

chr11-36575399-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1_SupportingPP4PS3_ModeratePM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: NM_000448.3(RAG1):c.2095C>T is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 699 (p.Arg699Trp).The filtering allele frequency (the upper threshold of the 95% CI of 5/1179830) of the c.2095C>T variant in RAG1 is 0.000001320 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).This missense variant is located in the core domain (amino acids 387-1011) (PM1_supporting).Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) Total :1.5 pts. (PMID:29107076) (PP4). The VDJ recombination activity was found to be 19.3 +/- 1.8 % of WT (mean +/- SE) in a flow cytometry based assay. PMID : 24290284 (PS3_Moderate).The patient (PMID:21771083) was found heterozygous for R699W & Y1001X (not yet curated by SCID VCEP); p.R699W & p.393fsX402 (not yet curated by SCID VCEP)(PMID:21184155); homozygous in 3 individuals (PMIDs: 24122031,31503426, 32447396) (Pt.: 1)(PM3).In summary, this variant meets the criteria to be classified as Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_Supporting, PP4,PS3_Moderate,PM3(VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA219824/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RAG1
NM_000448.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 4.25

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 Likely_pathogenic. Variant got 7 ACMG points.

PS3

PM1

PM2

PM3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG1	NM_000448.3 linkuse as main transcript	c.2095C>T	p.Arg699Trp	missense_variant	2/2	ENST00000299440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG1	ENST00000299440.6 linkuse as main transcript	c.2095C>T	p.Arg699Trp	missense_variant	2/2	1	NM_000448.3	P1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251100

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000993

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Dec 20, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Hacettepe Dept. of Bioinformatics Rare Diseases Research Center, Institute of Health Sciences	Feb 25, 2019	The c.2095C>T; p.Arg699Trp variant in RAG1 has been reported in several families with autosomal recessive Severe combined immunodeficiency, Omenn syndrome, and Combined cellular and humoral immune defects with granulomas) (Reiff 2013, Avila 2010, Zhang 2011, Lee 2011, Lee 2014). Besides, a ClinVar entry is present for this variant with the variation ID: 68689). The c.2095C>T; p.Arg699Trp was observed in the gnomAD database with a low minor allele frequency without any homozygous individuals (MAF: 0.0000142). In summary, the p.Arg699Trp variant meets our criteria to be classified as pathogenic along with previously published articles -

Histiocytic medullary reticulosis

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	PM2, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics Facility, Ludwig-Maximilians-Universität München	Dec 28, 2021	- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 699 of the RAG1 protein (p.Arg699Trp). This variant is present in population databases (rs199474676, gnomAD 0.02%). This missense change has been observed in individuals with RAG1-related diseases (PMID: 20956421, 21184155, 21771083, 24122031, 24290284). This variant is also known as 2219C>T. ClinVar contains an entry for this variant (Variation ID: 68689). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). This variant disrupts the p.Arg699 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 24290284), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Combined immunodeficiency due to partial RAG1 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 01, 2024

- -

not provided

Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Benign

0.18

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.86

Gain of loop (P = 0.0312);

MVP

0.96

MPC

0.76

ClinPred

0.99

GERP RS

1.4

Varity_R

0.63

gMVP

0.94

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