Genetic Variant RAG1:n.312C>T (chr11-36511020-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000529126.5(RAG1):n.312C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 152,232 control chromosomes in the GnomAD database, including 68,958 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.95 ( 68951 hom., cov: 32)

Exomes 𝑓: 1.0 ( 7 hom. )

Consequence

RAG1
ENST00000529126.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.295

Publications

3 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 Gene-Disease associations (from GenCC):

immunodeficiency disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
Omenn syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
recombinase activating gene 1 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
combined immunodeficiency due to partial RAG1 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
RAG1	NM_001440489.1 link	c.-33C>T	5_prime_UTR_variant	Exon 1 of 2	NP_001427418.1
RAG1	NM_001377277.1 link	c.-289+483C>T	intron_variant	Intron 1 of 4	NP_001364206.1
RAG1	NM_001377278.1 link	c.-227+483C>T	intron_variant	Intron 1 of 3	NP_001364207.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
RAG1	ENST00000529126.5 link	n.312C>T	non_coding_transcript_exon_variant	Exon 1 of 3	3
RAG1	ENST00000697713.1 link	c.-131+483C>T	intron_variant	Intron 1 of 2		ENSP00000513411.1	P15918-1
RAG1	ENST00000697714.1 link	c.-15+483C>T	intron_variant	Intron 1 of 1		ENSP00000513412.1	P15918-1
RAG1	ENST00000697715.1 link	c.-289+483C>T	intron_variant	Intron 1 of 4		ENSP00000513413.1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.949

AC:

144276

AN:

152100

Hom.:

68904

Cov.:

show subpopulations

Gnomad AFR

AF:

0.825

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.980

Gnomad ASJ

AF:

0.993

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.976

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.984

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.963

GnomAD4 exome

AF:

1.00

AC:

AN:

Hom.:

Cov.:

AF XY:

1.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

GnomAD4 genome

AF:

0.949

AC:

144381

AN:

152218

Hom.:

68951

Cov.:

AF XY:

0.950

AC XY:

70740

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.826

AC:

34241

AN:

41478

American (AMR)

AF:

0.980

AC:

14990

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.993

AC:

3449

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5176

AN:

5182

South Asian (SAS)

AF:

0.977

AC:

4719

AN:

4830

European-Finnish (FIN)

AF:

1.00

AC:

10610

AN:

10610

Middle Eastern (MID)

AF:

0.983

AC:

289

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67960

AN:

68036

Other (OTH)

AF:

0.963

AC:

2035

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

330

660

991

1321

1651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.967

Hom.:

99927

Bravo

AF:

0.943

Asia WGS

AF:

0.971

AC:

3377

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.0

(source)

DANN

Benign

0.56

PhyloP100

0.29

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over