dbSNP rs776052038: IRAG1:p.Gly731Ala (chr11-10591596-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_130385.4(IRAG1):c.2192G>C(p.Gly731Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,444,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G731E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IRAG1
NM_130385.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.55

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:

IRAG1-AS1 (HGNC:43434): (IRAG1 antisense RNA 1)

IRAG1-AS1 links:

LYVE1 (HGNC:14687): (lymphatic vessel endothelial hyaluronan receptor 1) This gene encodes a type I integral membrane glycoprotein. The encoded protein acts as a receptor and binds to both soluble and immobilized hyaluronan. This protein may function in lymphatic hyaluronan transport and have a role in tumor metastasis. [provided by RefSeq, Jul 2008]

LYVE1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21810684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG1	NM_130385.4 link	c.2192G>C	p.Gly731Ala	missense_variant	Exon 18 of 21	ENST00000423302.7	NP_569056.4	Q9Y6F6-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRAG1	ENST00000423302.7 link	c.2192G>C	p.Gly731Ala	missense_variant	Exon 18 of 21	2	NM_130385.4	ENSP00000412130.2	Q9Y6F6-7
IRAG1	ENST00000534266.6 link	c.1247G>C	p.Gly416Ala	missense_variant	Exon 16 of 19	2		ENSP00000433296.2	Q9Y6F6-6
IRAG1	ENST00000526414.5 link	n.*84G>C		non_coding_transcript_exon_variant	Exon 16 of 17	2		ENSP00000435658.1	E9PJ61
IRAG1	ENST00000526414.5 link	n.*84G>C		3_prime_UTR_variant	Exon 16 of 17	2		ENSP00000435658.1	E9PJ61

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000454

AC:

AN:

220194

Hom.:

AF XY:

0.00000848

AC XY:

AN XY:

117954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000375

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1444000

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;.;.;.;.;.;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;.;D;.;D;D;D;.

M_CAP

Benign

0.0072

MetaRNN

Benign

0.22

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

N;.;N;N;N;N;N;.

REVEL

Benign

0.11

Sift

Benign

0.059

T;.;D;T;D;D;D;.

Sift4G

Benign

0.76

T;T;T;T;T;T;T;T

Vest4

0.23

MVP

0.39

MPC

0.16

ClinPred

0.53

GERP RS

4.5

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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