11-36512203-G-A

Variant names:

• chr11-36512203-G-A
• rs5030411
• NM_001377277.1:c.-289+1666G>A

Variant summary

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

The NM_001377277.1(RAG1):​c.-289+1666G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 152,032 control chromosomes in the GnomAD database, including 21,497 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 0.50 (21497 hom., cov: 32)
• Consequence: RAG1 NM_001377277.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 19 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 = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_001377277.1	c.-289+1666G>A		intron_variant	Intron 1 of 4		NP_001364206.1
RAG1	NM_001377278.1	c.-227+1666G>A		intron_variant	Intron 1 of 3		NP_001364207.1
RAG1	NM_001377279.1	c.-129+1666G>A		intron_variant	Intron 1 of 2		NP_001364208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000697713.1	c.-131+1666G>A		intron_variant	Intron 1 of 2			ENSP00000513411.1
RAG1	ENST00000697714.1	c.-15+1666G>A		intron_variant	Intron 1 of 1			ENSP00000513412.1
RAG1	ENST00000697715.1	c.-289+1666G>A		intron_variant	Intron 1 of 4			ENSP00000513413.1
RAG1	ENST00000529126.5	n.330+1165G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75276 AN: 151914 Hom.: 21496 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.514

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

GnomAD4 genome AF: 0.495 AC: 75281 AN: 152032 Hom.: 21497 Cov.: 32 AF XY: 0.501 AC XY: 37219 AN XY: 74316

African (AFR) AF: 0.198 AC: 8212 AN: 41486

American (AMR) AF: 0.562 AC: 8580 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2010 AN: 3470

East Asian (EAS) AF: 0.722 AC: 3726 AN: 5160

South Asian (SAS) AF: 0.633 AC: 3050 AN: 4818

European-Finnish (FIN) AF: 0.628 AC: 6629 AN: 10550

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41181 AN: 67962

Other (OTH) AF: 0.517 AC: 1091 AN: 2112

Alfa AF: 0.563 Hom.: 70299

Bravo AF: 0.478

Asia WGS AF: 0.622 AC: 2166 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	4.3
DANN	Benign	0.69
PhyloP100		0.24

Splicing

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

Other links and lift over

dbSNP: rs5030411; hg19: chr11-36533753;