Variant X-108735113-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001379150.1(IRS4):c.1232G>A(p.Arg411Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,209,567 control chromosomes in the GnomAD database, including 1,524 homozygotes. There are 22,779 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.055 ( 149 hom., 1681 hem., cov: 22)

Exomes 𝑓: 0.059 ( 1375 hom. 21098 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:2

Conservation

PhyloP100: 0.0540

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016234219).

BP6

Variant X-108735113-C-T is Benign according to our data. Variant chrX-108735113-C-T is described in ClinVar as [Benign]. Clinvar id is 1284757.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-108735113-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IRS4	NM_001379150.1 linkuse as main transcript	c.1232G>A	p.Arg411Gln	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2 linkuse as main transcript	c.1232G>A	p.Arg411Gln	missense_variant	1/1
IRS4	XM_011531061.2 linkuse as main transcript	c.1232G>A	p.Arg411Gln	missense_variant	1/3
IRS4	XM_006724713.4 linkuse as main transcript	c.1232G>A	p.Arg411Gln	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4 linkuse as main transcript	c.1232G>A	p.Arg411Gln	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2 linkuse as main transcript	c.1232G>A	p.Arg411Gln	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes

AF:

0.0550

AC:

6137

AN:

111519

Hom.:

148

Cov.:

AF XY:

0.0497

AC XY:

1675

AN XY:

33691

show subpopulations

Gnomad AFR

AF:

0.0507

Gnomad AMI

AF:

0.0161

Gnomad AMR

AF:

0.0766

Gnomad ASJ

AF:

0.0413

Gnomad EAS

AF:

0.00113

Gnomad SAS

AF:

0.0565

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0636

Gnomad NFE

AF:

0.0597

Gnomad OTH

AF:

0.0669

GnomAD3 exomes

AF:

0.0541

AC:

9874

AN:

182612

Hom.:

213

AF XY:

0.0515

AC XY:

3466

AN XY:

67260

show subpopulations

Gnomad AFR exome

AF:

0.0547

Gnomad AMR exome

AF:

0.0839

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.000577

Gnomad SAS exome

AF:

0.0594

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0576

Gnomad OTH exome

AF:

0.0522

GnomAD4 exome

AF:

0.0589

AC:

64707

AN:

1097994

Hom.:

1375

Cov.:

AF XY:

0.0581

AC XY:

21098

AN XY:

363384

show subpopulations

Gnomad4 AFR exome

AF:

0.0513

Gnomad4 AMR exome

AF:

0.0815

Gnomad4 ASJ exome

AF:

0.0406

Gnomad4 EAS exome

AF:

0.000232

Gnomad4 SAS exome

AF:

0.0583

Gnomad4 FIN exome

AF:

0.0325

Gnomad4 NFE exome

AF:

0.0623

Gnomad4 OTH exome

AF:

0.0556

GnomAD4 genome

AF:

0.0551

AC:

6146

AN:

111573

Hom.:

149

Cov.:

AF XY:

0.0498

AC XY:

1681

AN XY:

33755

show subpopulations

Gnomad4 AFR

AF:

0.0507

Gnomad4 AMR

AF:

0.0769

Gnomad4 ASJ

AF:

0.0413

Gnomad4 EAS

AF:

0.00114

Gnomad4 SAS

AF:

0.0574

Gnomad4 FIN

AF:

0.0360

Gnomad4 NFE

AF:

0.0597

Gnomad4 OTH

AF:

0.0661

Alfa

AF:

0.0565

Hom.:

2596

Bravo

AF:

0.0575

TwinsUK

AF:

0.0634

AC:

235

ALSPAC

AF:

0.0640

AC:

185

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.00446

AC:

ExAC

AF:

0.0538

AC:

6536

EpiCase

AF:

0.0608

EpiControl

AF:

0.0591

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.9

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.017

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0030

Polyphen

0.25

Vest4

0.036

MPC

0.62

ClinPred

0.0011

GERP RS

2.2

Varity_R

0.093

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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