Variant X-108733493-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001379150.1(IRS4):c.2852C>T(p.Pro951Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,098,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 8 hem. )

Failed GnomAD Quality Control

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.07

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=0.15671536).

BP6

Variant X-108733493-G-A is Benign according to our data. Variant chrX-108733493-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2673253.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108733493-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IRS4	NM_001379150.1 linkuse as main transcript	c.2852C>T	p.Pro951Leu	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2 linkuse as main transcript	c.2852C>T	p.Pro951Leu	missense_variant	1/1
IRS4	XM_011531061.2 linkuse as main transcript	c.2852C>T	p.Pro951Leu	missense_variant	1/3
IRS4	XM_006724713.4 linkuse as main transcript	c.2852C>T	p.Pro951Leu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4 linkuse as main transcript	c.2852C>T	p.Pro951Leu	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2 linkuse as main transcript	c.2852C>T	p.Pro951Leu	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111735

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33919

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183459

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67889

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1098220

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363576

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000712

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111735

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33919

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

IRS4: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.60

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.99

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.046

Sift

Uncertain

0.024

Sift4G

Uncertain

0.037

Polyphen

0.030

Vest4

0.080

MutPred

0.45

Loss of disorder (P = 0.0562);

MVP

0.10

MPC

0.50

ClinPred

0.17

GERP RS

1.9

Varity_R

0.058

gMVP

0.27

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