Variant rs137853896 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001379150.1(IRS4):c.1315A>T(p.Ser439Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,210,186 control chromosomes in the GnomAD database, including 3 homozygotes. There are 295 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 Lovd as Benign (no stars).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., 23 hem., cov: 22)

Exomes 𝑓: 0.00073 ( 3 hom. 272 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.228

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005941719).

BP6

Variant X-108735030-T-A is Benign according to our data. Variant chrX-108735030-T-A is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1 linkuse as main transcript	c.1315A>T	p.Ser439Cys	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 linkuse as main transcript	c.1315A>T	p.Ser439Cys	missense_variant	1/1		NP_003595.1	O14654
IRS4	XM_011531061.2 linkuse as main transcript	c.1315A>T	p.Ser439Cys	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4 linkuse as main transcript	c.1315A>T	p.Ser439Cys	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4 linkuse as main transcript	c.1315A>T	p.Ser439Cys	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 linkuse as main transcript	c.1315A>T	p.Ser439Cys	missense_variant	1/1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.000608

AC:

AN:

111899

Hom.:

Cov.:

AF XY:

0.000675

AC XY:

AN XY:

34083

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000739

Gnomad FIN

AF:

0.00446

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000640

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00111

AC:

203

AN:

183389

Hom.:

AF XY:

0.00115

AC XY:

AN XY:

67829

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00638

Gnomad NFE exome

AF:

0.000904

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.000732

AC:

804

AN:

1098232

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

272

AN XY:

363590

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00632

Gnomad4 NFE exome

AF:

0.000555

Gnomad4 OTH exome

AF:

0.000477

GnomAD4 genome

AF:

0.000607

AC:

AN:

111954

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

34148

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000740

Gnomad4 FIN

AF:

0.00446

Gnomad4 NFE

AF:

0.000640

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000582

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.00112

AC:

136

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Uncertain

0.60

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.37

M_CAP

Benign

0.0089

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.019

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.0070

Vest4

0.040

MVP

0.068

MPC

0.58

ClinPred

0.022

GERP RS

-0.42

Varity_R

0.17

gMVP

0.64

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