Genetic Variant IRS4:p.Ala1072Val (chrX-108733130-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001379150.1(IRS4):c.3215C>T(p.Ala1072Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000231 in 1,209,620 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000020 ( 0 hom. 7 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.86

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40375948).

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1 link	c.3215C>T	p.Ala1072Val	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 link	c.3215C>T	p.Ala1072Val	missense_variant	Exon 1 of 1		NP_003595.1	O14654
IRS4	XM_011531061.2 link	c.3215C>T	p.Ala1072Val	missense_variant	Exon 1 of 3		XP_011529363.1
IRS4	XM_006724713.4 link	c.3215C>T	p.Ala1072Val	missense_variant	Exon 1 of 2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4 link	c.3215C>T	p.Ala1072Val	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 link	c.3215C>T	p.Ala1072Val	missense_variant	Exon 1 of 1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

112036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34220

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000940

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183438

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67872

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1097584

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362962

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:

0.0000250

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000536

AC:

AN:

112036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34220

show subpopulations

Gnomad4 AFR

AF:

0.0000325

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:

0.0000940

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 9

Uncertain:1

Feb 28, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.56

M_CAP

Benign

0.012

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.2

REVEL

Benign

0.17

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0070

Polyphen

0.0090

Vest4

0.64

MVP

0.32

MPC

0.49

ClinPred

0.60

GERP RS

4.5

Varity_R

0.14

gMVP

0.21

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