rs141560248

Positions:

chr11-36575875-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_000448.3(RAG1):c.2571C>T(p.Ala857=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,614,172 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 15 hom. )

Consequence

RAG1
NM_000448.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -0.0360

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 11-36575875-C-T is Benign according to our data. Variant chr11-36575875-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469113.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2}. Variant chr11-36575875-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.036 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG1	NM_000448.3 linkuse as main transcript	c.2571C>T	p.Ala857=	synonymous_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.2571C>T	p.Ala857=	synonymous_variant	2/2	1	NM_000448.3	P1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

346

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00266

AC:

667

AN:

250946

Hom.:

AF XY:

0.00284

AC XY:

385

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00278

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.00396

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00349

AC:

5095

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

2585

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00303

Gnomad4 FIN exome

AF:

0.00362

Gnomad4 NFE exome

AF:

0.00394

Gnomad4 OTH exome

AF:

0.00288

GnomAD4 genome

AF:

0.00227

AC:

346

AN:

152334

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00369

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00318

Hom.:

Bravo

AF:

0.00225

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	RAG1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 15, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Histiocytic medullary reticulosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2017

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. -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

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