rs1980131

Positions:

chr11-36576184-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000299440.6(RAG1):c.2880A>G(p.Ala960=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,614,052 control chromosomes in the GnomAD database, including 4,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 470 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4130 hom. )

Consequence

RAG1
ENST00000299440.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.427

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:9832): (recombination activating 2) This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms. [provided by RefSeq, Jul 2008]

RAG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-36576184-A-G is Benign according to our data. Variant chr11-36576184-A-G is described in ClinVar as [Benign]. Clinvar id is 256190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-36576184-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.427 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAG1	NM_000448.3 linkuse as main transcript	c.2880A>G	p.Ala960=	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.2880A>G	p.Ala960=	synonymous_variant	2/2	1	NM_000448.3	ENSP00000299440	P1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0750

AC:

11415

AN:

152104

Hom.:

471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0791

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0744

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0576

Gnomad FIN

AF:

0.0663

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0795

Gnomad OTH

AF:

0.0871

GnomAD3 exomes

AF:

0.0654

AC:

16371

AN:

250426

Hom.:

587

AF XY:

0.0661

AC XY:

8965

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.0767

Gnomad AMR exome

AF:

0.0489

Gnomad ASJ exome

AF:

0.0794

Gnomad EAS exome

AF:

0.00136

Gnomad SAS exome

AF:

0.0604

Gnomad FIN exome

AF:

0.0672

Gnomad NFE exome

AF:

0.0786

Gnomad OTH exome

AF:

0.0716

GnomAD4 exome

AF:

0.0735

AC:

107471

AN:

1461830

Hom.:

4130

Cov.:

AF XY:

0.0738

AC XY:

53644

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0776

Gnomad4 AMR exome

AF:

0.0503

Gnomad4 ASJ exome

AF:

0.0771

Gnomad4 EAS exome

AF:

0.00123

Gnomad4 SAS exome

AF:

0.0618

Gnomad4 FIN exome

AF:

0.0698

Gnomad4 NFE exome

AF:

0.0775

Gnomad4 OTH exome

AF:

0.0779

GnomAD4 genome

AF:

0.0751

AC:

11428

AN:

152222

Hom.:

470

Cov.:

AF XY:

0.0746

AC XY:

5549

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0793

Gnomad4 AMR

AF:

0.0742

Gnomad4 ASJ

AF:

0.0795

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0581

Gnomad4 FIN

AF:

0.0663

Gnomad4 NFE

AF:

0.0795

Gnomad4 OTH

AF:

0.0852

Alfa

AF:

0.0776

Hom.:

284

Bravo

AF:

0.0754

Asia WGS

AF:

0.0390

AC:

138

AN:

3478

EpiCase

AF:

0.0864

EpiControl

AF:

0.0803

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

-0.84

CADD

Benign

1.1

DANN

Benign

0.49

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