rs11042902

Variant names:

• chr11-10634076-C-T
• rs11042902
• NM_130385.4:c.226-5G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The ENST00000534266.6(IRAG1):​c.-670-2G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,585,126 control chromosomes in the GnomAD database, including 66,537 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5378 hom., cov: 31)
  • Exomes 𝑓: 0.28 (61159 hom.)
• Consequence: IRAG1 ENST00000534266.6 splice_acceptor, intron
• Scores: Splicing: ADA: 0.06107
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510

Genes affected

IRAG1 (HGNC:7237): (inositol 1,4,5-triphosphate receptor associated 1) This gene is similar to a putative mouse tumor suppressor gene (Mrvi1) that is frequently disrupted by mouse AIDS-related virus (MRV). The encoded protein, which is found in the membrane of the endoplasmic reticulum, is similar to Jaw1, a lymphoid-restricted protein whose expression is down-regulated during lymphoid differentiation. This protein is a substrate of cGMP-dependent kinase-1 (PKG1) that can function as a regulator of IP3-induced calcium release. Studies in mouse suggest that MRV integration at Mrvi1 induces myeloid leukemia by altering the expression of a gene important for myeloid cell growth and/or differentiation, and thus this gene may function as a myeloid leukemia tumor suppressor gene. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene, and alternative translation start sites, including a non-AUG (CUG) start site, are used. [provided by RefSeq, May 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.059643254 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of 0 (no position change), new splice context is: gtgtttttgttctaaaccAGcag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG1	NM_130385.4	c.226-5G>A		splice_region_variant, intron_variant	Intron 2 of 20	ENST00000423302.7	NP_569056.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAG1	ENST00000423302.7	c.226-5G>A		splice_region_variant, intron_variant	Intron 2 of 20	2	NM_130385.4	ENSP00000412130.2
IRAG1	ENST00000534266.6	c.-670-2G>A		splice_acceptor_variant, intron_variant	Intron 1 of 18	2		ENSP00000433296.2
IRAG1	ENST00000526414.5	n.70-2G>A		splice_acceptor_variant, intron_variant	Intron 2 of 16	2		ENSP00000435658.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38581 AN: 151808 Hom.: 5380 Cov.: 31

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.0201

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.247 AC: 56221 AN: 227246 AF XY: 0.249

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.0223

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.283 AC: 406074 AN: 1433200 Hom.: 61159 Cov.: 24 AF XY: 0.281 AC XY: 199911 AN XY: 712534

Gnomad4 AFR exome AF: 0.193 AC: 6350 AN: 32948

Gnomad4 AMR exome AF: 0.158 AC: 6752 AN: 42654

Gnomad4 ASJ exome AF: 0.304 AC: 7801 AN: 25698

Gnomad4 EAS exome AF: 0.0115 AC: 449 AN: 39082

Gnomad4 SAS exome AF: 0.159 AC: 13259 AN: 83224

Gnomad4 FIN exome AF: 0.338 AC: 17763 AN: 52526

Gnomad4 NFE exome AF: 0.308 AC: 336266 AN: 1091868

Gnomad4 Remaining exome AF: 0.268 AC: 15918 AN: 59474

GnomAD4 genome AF: 0.254 AC: 38590 AN: 151926 Hom.: 5378 Cov.: 31 AF XY: 0.253 AC XY: 18771 AN XY: 74236

Gnomad4 AFR AF: 0.194 AC: 0.194137 AN: 0.194137

Gnomad4 AMR AF: 0.213 AC: 0.213135 AN: 0.213135

Gnomad4 ASJ AF: 0.306 AC: 0.306228 AN: 0.306228

Gnomad4 EAS AF: 0.0200 AC: 0.0199612 AN: 0.0199612

Gnomad4 SAS AF: 0.172 AC: 0.171797 AN: 0.171797

Gnomad4 FIN AF: 0.341 AC: 0.34116 AN: 0.34116

Gnomad4 NFE AF: 0.305 AC: 0.304785 AN: 0.304785

Gnomad4 OTH AF: 0.250 AC: 0.249763 AN: 0.249763

Alfa AF: 0.287 Hom.: 22034

Bravo AF: 0.244

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.3
DANN	Benign	0.79
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.061
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11042902; hg19: chr11-10655623; COSMIC: COSV70212057; COSMIC: COSV70212057;