rs5030490

Variant names:

• chr11-36512635-T-C
• rs5030490
• NM_001377277.1:c.-289+2098T>C

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+2098T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 152,310 control chromosomes in the GnomAD database, including 35 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 0.013 (35 hom., cov: 33)
• Consequence: RAG1 NM_001377277.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 2 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 = 0.0699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_001377277.1	c.-289+2098T>C		intron_variant	Intron 1 of 4		NP_001364206.1
RAG1	NM_001377278.1	c.-227+2098T>C		intron_variant	Intron 1 of 3		NP_001364207.1
RAG1	NM_001377279.1	c.-129+2098T>C		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+2098T>C		intron_variant	Intron 1 of 2			ENSP00000513411.1
RAG1	ENST00000697714.1	c.-15+2098T>C		intron_variant	Intron 1 of 1			ENSP00000513412.1
RAG1	ENST00000697715.1	c.-289+2098T>C		intron_variant	Intron 1 of 4			ENSP00000513413.1
RAG1	ENST00000529126.5	n.330+1597T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2044 AN: 152192 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0762

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0119

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

GnomAD4 genome AF: 0.0134 AC: 2044 AN: 152310 Hom.: 35 Cov.: 33 AF XY: 0.0131 AC XY: 977 AN XY: 74466

African (AFR) AF: 0.00330 AC: 137 AN: 41568

American (AMR) AF: 0.0160 AC: 245 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.0761 AC: 395 AN: 5188

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4824

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 999 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0137 Hom.: 9

Bravo AF: 0.0154

Asia WGS AF: 0.0330 AC: 115 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	5.3
DANN	Benign	0.62
PhyloP100		1.1

Splicing

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

Other links and lift over

dbSNP: rs5030490; hg19: chr11-36534185;