X-108733320-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001379150.1(IRS4):c.3025G>T(p.Ala1009Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,210,101 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., 22 hem., cov: 23)

Exomes 𝑓: 0.000096 ( 0 hom. 23 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0750

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00328663).

BP6

Variant X-108733320-C-A is Benign according to our data. Variant chrX-108733320-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3060972.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IRS4	NM_001379150.1 linkuse as main transcript	c.3025G>T	p.Ala1009Ser	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2 linkuse as main transcript	c.3025G>T	p.Ala1009Ser	missense_variant	1/1
IRS4	XM_011531061.2 linkuse as main transcript	c.3025G>T	p.Ala1009Ser	missense_variant	1/3
IRS4	XM_006724713.4 linkuse as main transcript	c.3025G>T	p.Ala1009Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4 linkuse as main transcript	c.3025G>T	p.Ala1009Ser	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2 linkuse as main transcript	c.3025G>T	p.Ala1009Ser	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes

AF:

0.000661

AC:

AN:

111933

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

34107

show subpopulations

Gnomad AFR

AF:

0.00231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000283

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

GnomAD3 exomes

AF:

0.000234

AC:

AN:

183447

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

67881

show subpopulations

Gnomad AFR exome

AF:

0.00266

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000956

AC:

105

AN:

1098116

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363470

show subpopulations

Gnomad4 AFR exome

AF:

0.00295

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.000661

AC:

AN:

111985

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

34169

show subpopulations

Gnomad4 AFR

AF:

0.00230

Gnomad4 AMR

AF:

0.000283

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

Alfa

AF:

0.0000722

Hom.:

Bravo

AF:

0.000824

ESP6500AA

AF:

0.00235

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

IRS4-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.18

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.43

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

0.30

REVEL

Benign

0.044

Sift

Benign

0.20

Sift4G

Benign

0.18

Polyphen

0.42

Vest4

0.065

MVP

0.21

MPC

0.45

ClinPred

0.010

GERP RS

-0.17

Varity_R

0.099

gMVP

0.17

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