Genetic Variant ENST00000534266.6:c.-838A>G (chr11-10652192-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

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 Benign. Variant got -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 link	c.68-10A>G		intron_variant	Intron 1 of 20	ENST00000423302.7	NP_569056.4	Q9Y6F6-7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRAG1	ENST00000534266.6 link	c.-838A>G	5_prime_UTR_variant	Exon 1 of 19	2		ENSP00000433296.2	Q9Y6F6-6
IRAG1	ENST00000423302.7 link	c.68-10A>G	intron_variant	Intron 1 of 20	2	NM_130385.4	ENSP00000412130.2	Q9Y6F6-7
IRAG1	ENST00000526414.5 link	n.-89-10A>G	intron_variant	Intron 1 of 16	2		ENSP00000435658.1	E9PJ61

Frequencies

GnomAD3 genomes

AF:

0.780

AC:

118550

AN:

152072

Hom.:

47432

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.762

AC:

188760

AN:

247596

Hom.:

73696

AF XY:

0.758

AC XY:

101863

AN XY:

134324

show subpopulations

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 SAS exome

AF:

0.859

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.:

AF XY:

0.718

AC XY:

521751

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.950

Gnomad4 AMR exome

AF:

0.847

Gnomad4 ASJ exome

AF:

0.707

Gnomad4 EAS exome

AF:

0.989

Gnomad4 SAS exome

AF:

0.856

Gnomad4 FIN exome

AF:

0.667

Gnomad4 NFE exome

AF:

0.685

Gnomad4 OTH exome

AF:

0.733

GnomAD4 genome

AF:

0.780

AC:

118663

AN:

152190

Hom.:

47485

Cov.:

AF XY:

0.781

AC XY:

58083

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.944

Gnomad4 AMR

AF:

0.785

Gnomad4 ASJ

AF:

0.706

Gnomad4 EAS

AF:

0.979

Gnomad4 SAS

AF:

0.847

Gnomad4 FIN

AF:

0.672

Gnomad4 NFE

AF:

0.683

Gnomad4 OTH

AF:

0.774

Alfa

AF:

0.704

Hom.:

97406

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

BayesDel_noAF

Benign

-0.86

CADD

Benign

DANN

Benign

0.54

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.27

MetaRNN

Benign

5.5e-7

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.050

REVEL

Benign

0.054

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.028

ClinPred

0.021

GERP RS

-2.6

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

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