rs1980131

Variant summary

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

The ENST00000299440.6(RAG1):ā€‹c.2880A>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.075 ( 470 hom., cov: 32)
Exomes š‘“: 0.074 ( 4130 hom. )

Consequence

RAG1
ENST00000299440.6 synonymous

Scores

2

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]
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]

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
RAG1NM_000448.3 linkuse as main transcriptc.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
RAG1ENST00000299440.6 linkuse as main transcriptc.2880A>G p.Ala960= synonymous_variant 2/21 NM_000448.3 ENSP00000299440 P1P15918-1

Frequencies

GnomAD3 genomes
AF:
0.0750
AC:
11415
AN:
152104
Hom.:
471
Cov.:
32
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.:
34
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.:
32
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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 07, 2023- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not provided, no classification providedphenotyping onlyGenomeConnect, 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 submitterclinical testingGeneDxMar 03, 2015- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 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.

Other links and lift over

dbSNP: rs1980131; hg19: chr11-36597734; COSMIC: COSV55026991; API