Variant 11-36573386-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000448.3:c.82T>C variant in RAG1 is a missense variant predicted to cause a substitution of tryptophan by arginine at amino acid 28 (p.Trp28Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV001210547.4). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA380145403/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAG1
NM_000448.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 7.66

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_000448.3 link	c.82T>C	p.Trp28Arg	missense_variant	Exon 2 of 2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6 link	c.82T>C	p.Trp28Arg	missense_variant	Exon 2 of 2	1	NM_000448.3	ENSP00000299440.5		P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Recombinase activating gene 1 deficiency

Uncertain:1

Apr 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000448.3:c.82T>C variant in RAG1 is a missense variant predicted to cause a substitution of tryptophan by arginine at amino acid 28 (p.Trp28Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV001210547.4). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). -

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

Uncertain:1

Jan 20, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RAG1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 28 of the RAG1 protein (p.Trp28Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

2.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.77

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.86

MutPred

0.61

Gain of disorder (P = 0.0129);

MVP

0.98

MPC

1.0

ClinPred

0.96

GERP RS

6.1

Varity_R

0.58

gMVP

0.55

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