Genetic Variant RAG1:c.-115T>G (chr11-36510938-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001440489.1(RAG1):c.-115T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,216 control chromosomes in the GnomAD database, including 1,609 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 0.14 ( 1609 hom., cov: 32)

Exomes 𝑓: 0.18 ( 0 hom. )

Consequence

RAG1
NM_001440489.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.188

Publications

12 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: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
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=-0.78).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440489.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
RAG1	NM_001440489.1	c.-115T>G	5_prime_UTR	Exon 1 of 2	NP_001427418.1
RAG1	NM_001377277.1	c.-289+401T>G	intron	N/A	NP_001364206.1	P15918-1
RAG1	NM_001377278.1	c.-227+401T>G	intron	N/A	NP_001364207.1	P15918-1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
RAG1	ENST00000697713.1	c.-131+401T>G	intron	N/A	ENSP00000513411.1	P15918-1
RAG1	ENST00000697714.1	c.-15+401T>G	intron	N/A	ENSP00000513412.1	P15918-1
RAG1	ENST00000697715.1	c.-289+401T>G	intron	N/A	ENSP00000513413.1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21703

AN:

152076

Hom.:

1609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.0778

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.137

GnomAD4 exome

AF:

0.182

AC:

AN:

Hom.:

Cov.:

AF XY:

0.200

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)

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.143

AC:

21715

AN:

152194

Hom.:

1609

Cov.:

AF XY:

0.143

AC XY:

10668

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.152

AC:

6319

AN:

41528

American (AMR)

AF:

0.199

AC:

3034

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

348

AN:

3472

East Asian (EAS)

AF:

0.148

AC:

766

AN:

5172

South Asian (SAS)

AF:

0.0779

AC:

376

AN:

4828

European-Finnish (FIN)

AF:

0.136

AC:

1445

AN:

10600

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9040

AN:

67990

Other (OTH)

AF:

0.136

AC:

288

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

973

1946

2918

3891

4864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.128

Hom.:

2811

Bravo

AF:

0.150

Asia WGS

AF:

0.137

AC:

479

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.8

(source)

DANN

Benign

0.69

PhyloP100

0.19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over