rs17847227

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379150.1(IRS4):c.3472G>A(p.Ala1158Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,167,324 control chromosomes in the GnomAD database, including 32 homozygotes. There are 1,039 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 9 hom., 232 hem., cov: 23)

Exomes 𝑓: 0.0021 ( 23 hom. 807 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.657

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033047497).

BP6

Variant X-108732873-C-T is Benign according to our data. Variant chrX-108732873-C-T is described in ClinVar as [Benign]. Clinvar id is 713320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108732873-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0067 (753/112383) while in subpopulation EAS AF= 0.0474 (168/3545). AF 95% confidence interval is 0.0415. There are 9 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1 link	c.3472G>A	p.Ala1158Thr	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 link	c.3472G>A	p.Ala1158Thr	missense_variant	Exon 1 of 1		NP_003595.1	O14654
IRS4	XM_011531061.2 link	c.3472G>A	p.Ala1158Thr	missense_variant	Exon 1 of 3		XP_011529363.1
IRS4	XM_006724713.4 link	c.3472G>A	p.Ala1158Thr	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.3472G>A	p.Ala1158Thr	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 link	c.3472G>A	p.Ala1158Thr	missense_variant	Exon 1 of 1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.00667

AC:

749

AN:

112330

Hom.:

Cov.:

AF XY:

0.00673

AC XY:

232

AN XY:

34492

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00486

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0475

Gnomad SAS

AF:

0.0140

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000131

Gnomad OTH

AF:

0.00736

GnomAD3 exomes

AF:

0.00671

AC:

978

AN:

145752

Hom.:

AF XY:

0.00634

AC XY:

301

AN XY:

47496

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0457

Gnomad SAS exome

AF:

0.0185

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000295

Gnomad OTH exome

AF:

0.00574

GnomAD4 exome

AF:

0.00205

AC:

2167

AN:

1054941

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

807

AN XY:

339237

show subpopulations

Gnomad4 AFR exome

AF:

0.0123

Gnomad4 AMR exome

AF:

0.00140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0285

Gnomad4 SAS exome

AF:

0.0136

Gnomad4 FIN exome

AF:

0.0000523

Gnomad4 NFE exome

AF:

0.0000451

Gnomad4 OTH exome

AF:

0.00644

GnomAD4 genome

AF:

0.00670

AC:

753

AN:

112383

Hom.:

Cov.:

AF XY:

0.00671

AC XY:

232

AN XY:

34555

show subpopulations

Gnomad4 AFR

AF:

0.0153

Gnomad4 AMR

AF:

0.00485

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0474

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00991

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.00641

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.0139

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00617

AC:

743

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.54

REVEL

Benign

0.034

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.037

Polyphen

0.80

Vest4

0.062

MVP

0.33

MPC

0.48

ClinPred

0.014

GERP RS

3.8

Varity_R

0.13

gMVP

0.20

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