Variant X-108732657-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379150.1(IRS4):c.3688G>T(p.Asp1230Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,209,955 control chromosomes in the GnomAD database, including 199 homozygotes. There are 1,566 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 108 hom., 747 hem., cov: 23)

Exomes 𝑓: 0.0027 ( 91 hom. 819 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.830

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=0.0016138852).

BP6

Variant X-108732657-C-A is Benign according to our data. Variant chrX-108732657-C-A is described in ClinVar as [Benign]. Clinvar id is 777819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108732657-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1 linkuse as main transcript	c.3688G>T	p.Asp1230Tyr	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 linkuse as main transcript	c.3688G>T	p.Asp1230Tyr	missense_variant	1/1		NP_003595.1	O14654
IRS4	XM_011531061.2 linkuse as main transcript	c.3688G>T	p.Asp1230Tyr	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4 linkuse as main transcript	c.3688G>T	p.Asp1230Tyr	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.3688G>T	p.Asp1230Tyr	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 linkuse as main transcript	c.3688G>T	p.Asp1230Tyr	missense_variant	1/1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

2840

AN:

111662

Hom.:

108

Cov.:

AF XY:

0.0221

AC XY:

748

AN XY:

33832

show subpopulations

Gnomad AFR

AF:

0.0874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000376

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.00742

AC:

1362

AN:

183509

Hom.:

AF XY:

0.00470

AC XY:

319

AN XY:

67943

show subpopulations

Gnomad AFR exome

AF:

0.0924

Gnomad AMR exome

AF:

0.00438

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00274

AC:

3008

AN:

1098239

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

819

AN XY:

363595

show subpopulations

Gnomad4 AFR exome

AF:

0.0937

Gnomad4 AMR exome

AF:

0.00500

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000332

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000606

Gnomad4 OTH exome

AF:

0.00616

GnomAD4 genome

AF:

0.0254

AC:

2839

AN:

111716

Hom.:

108

Cov.:

AF XY:

0.0220

AC XY:

747

AN XY:

33896

show subpopulations

Gnomad4 AFR

AF:

0.0872

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000377

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.0165

Alfa

AF:

0.00361

Hom.:

110

Bravo

AF:

0.0295

ESP6500AA

AF:

0.0900

AC:

345

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00814

AC:

988

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

.;T

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.9

D;N

REVEL

Benign

0.12

Sift

Benign

0.34

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.86

.;P

Vest4

0.095

MVP

0.40

MPC

0.61

ClinPred

0.060

GERP RS

3.5

Varity_R

0.15

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