Variant X-108733652-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001379150.1(IRS4):c.2693G>A(p.Gly898Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,864 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10

Variant links:

Genes affected

IRS4 (HGNC:6128): (insulin receptor substrate 4) IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008]

IRS4 links:

Genome browser will be placed here

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=0.19498372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IRS4	NM_001379150.1 linkuse as main transcript	c.2693G>A	p.Gly898Glu	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2 linkuse as main transcript	c.2693G>A	p.Gly898Glu	missense_variant	1/1
IRS4	XM_011531061.2 linkuse as main transcript	c.2693G>A	p.Gly898Glu	missense_variant	1/3
IRS4	XM_006724713.4 linkuse as main transcript	c.2693G>A	p.Gly898Glu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4 linkuse as main transcript	c.2693G>A	p.Gly898Glu	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2 linkuse as main transcript	c.2693G>A	p.Gly898Glu	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111638

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33822

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363580

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111638

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33822

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.2693G>A (p.G898E) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a G to A substitution at nucleotide position 2693, causing the glycine (G) at amino acid position 898 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.45

M_CAP

Benign

0.040

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.93

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.037

Vest4

0.13

MutPred

0.35

Gain of solvent accessibility (P = 0.012);

MVP

0.15

MPC

0.64

ClinPred

0.56

GERP RS

3.4

Varity_R

0.20

gMVP

0.26

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over