X-108732617-A-C

Position:

• chrX-108732617-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001379150.1(IRS4):​c.3728T>G​(p.Phe1243Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32557732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3728T>G	p.Phe1243Cys	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3728T>G	p.Phe1243Cys	missense_variant	1/1		NP_003595.1
IRS4	XM_011531061.2	c.3728T>G	p.Phe1243Cys	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4	c.3728T>G	p.Phe1243Cys	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.3728T>G	p.Phe1243Cys	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3728T>G	p.Phe1243Cys	missense_variant	1/1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.0	D;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	.;D
Vest4		0.79
MutPred		0.20		.;Gain of catalytic residue at M1241 (P = 4e-04);
MVP		0.56
MPC		0.71
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.25
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107975847;