Variant X-108732669-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001379150.1(IRS4):c.3676C>A(p.Pro1226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,098,213 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000023 ( 0 hom. 6 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06737661).

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1 linkuse as main transcript	c.3676C>A	p.Pro1226Thr	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2 linkuse as main transcript	c.3676C>A	p.Pro1226Thr	missense_variant	1/1		NP_003595.1	O14654
IRS4	XM_011531061.2 linkuse as main transcript	c.3676C>A	p.Pro1226Thr	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4 linkuse as main transcript	c.3676C>A	p.Pro1226Thr	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.3676C>A	p.Pro1226Thr	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 linkuse as main transcript	c.3676C>A	p.Pro1226Thr	missense_variant	1/1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000136

AC:

AN:

183499

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

67941

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000912

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1098213

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363571

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000710

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.3676C>A (p.P1226T) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a C to A substitution at nucleotide position 3676, causing the proline (P) at amino acid position 1226 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;L

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-8.0

D;N

REVEL

Benign

0.034

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.61

.;P

Vest4

0.14

MutPred

0.20

.;Gain of phosphorylation at P1226 (P = 0.0019);

MVP

0.24

MPC

0.55

ClinPred

0.27

GERP RS

3.5

Varity_R

0.14

gMVP

0.12

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