Variant rs11042902 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_ModerateBA1

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

Variant links:

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]

IRAG1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 link	c.226-5G>A		splice_region_variant, intron_variant	Intron 2 of 20	ENST00000423302.7	NP_569056.4	Q9Y6F6-7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRAG1	ENST00000423302.7 link	c.226-5G>A	splice_region_variant, intron_variant	Intron 2 of 20	2	NM_130385.4	ENSP00000412130.2	Q9Y6F6-7
IRAG1	ENST00000534266.6 link	c.-670-2G>A	splice_acceptor_variant, intron_variant	Intron 1 of 18	2		ENSP00000433296.2	Q9Y6F6-6
IRAG1	ENST00000526414.5 link	n.70-2G>A	splice_acceptor_variant, intron_variant	Intron 2 of 16	2		ENSP00000435658.1	E9PJ61

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38581

AN:

151808

Hom.:

5380

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.247

AC:

56221

AN:

227246

Hom.:

7863

AF XY:

0.249

AC XY:

30556

AN XY:

122616

show subpopulations

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 SAS exome

AF:

0.159

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.:

AF XY:

0.281

AC XY:

199911

AN XY:

712534

show subpopulations

Gnomad4 AFR exome

AF:

0.193

Gnomad4 AMR exome

AF:

0.158

Gnomad4 ASJ exome

AF:

0.304

Gnomad4 EAS exome

AF:

0.0115

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.338

Gnomad4 NFE exome

AF:

0.308

Gnomad4 OTH exome

AF:

0.268

GnomAD4 genome

AF:

0.254

AC:

38590

AN:

151926

Hom.:

5378

Cov.:

AF XY:

0.253

AC XY:

18771

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.194

Gnomad4 AMR

AF:

0.213

Gnomad4 ASJ

AF:

0.306

Gnomad4 EAS

AF:

0.0200

Gnomad4 SAS

AF:

0.172

Gnomad4 FIN

AF:

0.341

Gnomad4 NFE

AF:

0.305

Gnomad4 OTH

AF:

0.250

Alfa

AF:

0.291

Hom.:

10301

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over