11-36518999-C-T

Variant names:

• chr11-36518999-C-T
• rs331455
• ENST00000534663.1:n.-568-1133C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000534663.1(RAG1):​n.-568-1133C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 152,136 control chromosomes in the GnomAD database, including 40,887 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 0.73 (40887 hom., cov: 33)
• Consequence: RAG1 ENST00000534663.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 13 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_001377277.1	c.-288-1133C>T		intron_variant	Intron 1 of 4		NP_001364206.1
RAG1	NM_001377278.1	c.-226-1133C>T		intron_variant	Intron 1 of 3		NP_001364207.1
RAG1	NM_001377279.1	c.-129+8462C>T		intron_variant	Intron 1 of 2		NP_001364208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000534663.1	n.-568-1133C>T		intron_variant	Intron 1 of 9	1		ENSP00000434610.1
RAG1	ENST00000697713.1	c.-131+8462C>T		intron_variant	Intron 1 of 2			ENSP00000513411.1
RAG1	ENST00000697714.1	c.-15+8462C>T		intron_variant	Intron 1 of 1			ENSP00000513412.1

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111191 AN: 152018 Hom.: 40863 Cov.: 33

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.726

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.731 AC: 111263 AN: 152136 Hom.: 40887 Cov.: 33 AF XY: 0.736 AC XY: 54714 AN XY: 74386

African (AFR) AF: 0.666 AC: 27638 AN: 41480

American (AMR) AF: 0.795 AC: 12145 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2379 AN: 3472

East Asian (EAS) AF: 0.916 AC: 4754 AN: 5190

South Asian (SAS) AF: 0.716 AC: 3454 AN: 4824

European-Finnish (FIN) AF: 0.765 AC: 8097 AN: 10582

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.740 AC: 50344 AN: 67988

Other (OTH) AF: 0.727 AC: 1537 AN: 2114

Alfa AF: 0.738 Hom.: 68646

Bravo AF: 0.734

Asia WGS AF: 0.796 AC: 2770 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	7.8
DANN	Benign	0.56
PhyloP100		1.2

Splicing

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

Other links and lift over

dbSNP: rs331455; hg19: chr11-36540549;