rs1980131

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000448.3(RAG1):c.2880A>G(p.Ala960Ala) 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
NM_000448.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.427

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Omenn syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
recombinase activating gene 2 deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

RAG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 256190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
RAG1	NM_000448.3 link	c.2880A>G	p.Ala960Ala	synonymous_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.2880A>G	p.Ala960Ala	synonymous_variant	Exon 2 of 2	1	NM_000448.3	ENSP00000299440.5		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

GnomAD2 exomes

AF:

0.0654

AC:

16371

AN:

250426

AF XY:

0.0661

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 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

African (AFR)

AF:

0.0776

AC:

2597

AN:

33478

American (AMR)

AF:

0.0503

AC:

2248

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0771

AC:

2015

AN:

26136

East Asian (EAS)

AF:

0.00123

AC:

AN:

39700

South Asian (SAS)

AF:

0.0618

AC:

5333

AN:

86258

European-Finnish (FIN)

AF:

0.0698

AC:

3727

AN:

53370

Middle Eastern (MID)

AF:

0.0999

AC:

576

AN:

5768

European-Non Finnish (NFE)

AF:

0.0775

AC:

86223

AN:

1112002

Other (OTH)

AF:

0.0779

AC:

4703

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6441

12882

19322

25763

32204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3118

6236

9354

12472

15590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0751

AC:

11428

AN:

152222

Hom.:

470

Cov.:

AF XY:

0.0746

AC XY:

5549

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0793

AC:

3292

AN:

41528

American (AMR)

AF:

0.0742

AC:

1135

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3472

East Asian (EAS)

AF:

0.00232

AC:

AN:

5178

South Asian (SAS)

AF:

0.0581

AC:

280

AN:

4822

European-Finnish (FIN)

AF:

0.0663

AC:

704

AN:

10612

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0795

AC:

5406

AN:

67994

Other (OTH)

AF:

0.0852

AC:

180

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

534

1068

1603

2137

2671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0761

Hom.:

371

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.1

(source)

DANN

Benign

0.49

PhyloP100

-0.43

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over