chr11-10652192-T-C

Variant names:

• chr11-10652192-T-C
• rs4909945
• ENST00000534266.6:c.-838A>G

Variant summary

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

The ENST00000534266.6(IRAG1):​c.-838A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 1,613,118 control chromosomes in the GnomAD database, including 427,069 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 0.78 (47485 hom., cov: 32)
  • Exomes 𝑓: 0.72 (379584 hom.)
• Consequence: IRAG1 ENST00000534266.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 51 publications found

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.473107E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG1	NM_130385.4	c.68-10A>G		intron_variant	Intron 1 of 20	ENST00000423302.7	NP_569056.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAG1	ENST00000534266.6	c.-838A>G		5_prime_UTR_variant	Exon 1 of 19	2		ENSP00000433296.2
IRAG1	ENST00000423302.7	c.68-10A>G		intron_variant	Intron 1 of 20	2	NM_130385.4	ENSP00000412130.2
IRAG1	ENST00000526414.5	n.-89-10A>G		intron_variant	Intron 1 of 16	2		ENSP00000435658.1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118550 AN: 152072 Hom.: 47432 Cov.: 32

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.774

GnomAD2 exomes AF: 0.762 AC: 188760 AN: 247596 AF XY: 0.758

Gnomad AFR exome AF: 0.950

Gnomad AMR exome AF: 0.855

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.979

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.673

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.716 AC: 1045951 AN: 1460928 Hom.: 379584 Cov.: 64 AF XY: 0.718 AC XY: 521751 AN XY: 726664

African (AFR) AF: 0.950 AC: 31809 AN: 33472

American (AMR) AF: 0.847 AC: 37823 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 18472 AN: 26110

East Asian (EAS) AF: 0.989 AC: 39243 AN: 39684

South Asian (SAS) AF: 0.856 AC: 73755 AN: 86162

European-Finnish (FIN) AF: 0.667 AC: 35525 AN: 53296

Middle Eastern (MID) AF: 0.694 AC: 4001 AN: 5764

European-Non Finnish (NFE) AF: 0.685 AC: 761104 AN: 1111438

Other (OTH) AF: 0.733 AC: 44219 AN: 60346

GnomAD4 genome AF: 0.780 AC: 118663 AN: 152190 Hom.: 47485 Cov.: 32 AF XY: 0.781 AC XY: 58083 AN XY: 74382

African (AFR) AF: 0.944 AC: 39237 AN: 41562

American (AMR) AF: 0.785 AC: 12009 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2450 AN: 3470

East Asian (EAS) AF: 0.979 AC: 5057 AN: 5164

South Asian (SAS) AF: 0.847 AC: 4084 AN: 4824

European-Finnish (FIN) AF: 0.672 AC: 7108 AN: 10576

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.683 AC: 46429 AN: 67976

Other (OTH) AF: 0.774 AC: 1636 AN: 2114

Alfa AF: 0.715 Hom.: 193545

Bravo AF: 0.794

TwinsUK AF: 0.694 AC: 2572

ALSPAC AF: 0.682 AC: 2627

ESP6500AA AF: 0.943 AC: 3796

ESP6500EA AF: 0.688 AC: 5768

ExAC AF: 0.760 AC: 91798

Asia WGS AF: 0.910 AC: 3162 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.671

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.54
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.054
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.028
ClinPred		0.021	T
GERP RS		-2.6
PromoterAI		-0.015	Neutral
Mutation Taster		=297/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4909945; hg19: chr11-10673739; COSMIC: COSV70210919; COSMIC: COSV70210919;