Variant chrX-108733710-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001379150.1(IRS4):c.2635C>T(p.His879Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,208,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Exomes 𝑓: 0.000056 ( 0 hom. 18 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.19

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048670232).

BS2

High Hemizygotes in GnomAdExome4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1 linkuse as main transcript	c.2635C>T	p.His879Tyr	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 linkuse as main transcript	c.2635C>T	p.His879Tyr	missense_variant	1/1		NP_003595.1	O14654
IRS4	XM_011531061.2 linkuse as main transcript	c.2635C>T	p.His879Tyr	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4 linkuse as main transcript	c.2635C>T	p.His879Tyr	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.2635C>T	p.His879Tyr	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 linkuse as main transcript	c.2635C>T	p.His879Tyr	missense_variant	1/1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.00000905

AC:

AN:

110524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32772

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183438

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

67898

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:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000733

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000565

AC:

AN:

1098238

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

363592

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000677

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000905

AC:

AN:

110524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32772

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000342

Hom.:

5708

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.91

CADD

Benign

8.4

DANN

Benign

0.97

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.30

M_CAP

Benign

0.0067

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.81

REVEL

Benign

0.044

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.047

Polyphen

0.0020

Vest4

0.071

MutPred

0.26

Gain of phosphorylation at H879 (P = 0.0014);

MVP

0.082

MPC

0.57

ClinPred

0.066

GERP RS

4.2

Varity_R

0.11

gMVP

0.082

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