X-108732755-G-A

Position:

• chrX-108732755-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001379150.1(IRS4):​c.3590C>T​(p.Ala1197Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.370

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047204435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS4	NM_001379150.1	c.3590C>T	p.Ala1197Val	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2	c.3590C>T	p.Ala1197Val	missense_variant	1/1
IRS4	XM_011531061.2	c.3590C>T	p.Ala1197Val	missense_variant	1/3
IRS4	XM_006724713.4	c.3590C>T	p.Ala1197Val	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4	c.3590C>T	p.Ala1197Val	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2	c.3590C>T	p.Ala1197Val	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.3590C>T (p.A1197V) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a C to T substitution at nucleotide position 3590, causing the alanine (A) at amino acid position 1197 to be replaced by a valine (V). 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	0.16
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.8
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.0090
Sift	Benign	0.33	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.045
MutPred		0.13		Loss of helix (P = 0.0376);
MVP		0.15
MPC		0.49
ClinPred		0.098	T
GERP RS		-1.0
Varity_R		0.032
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107975985;