X-108732630-C-T

Position:

• chrX-108732630-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001379150.1(IRS4):​c.3715G>A​(p.Val1239Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,218 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.800

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24572244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3715G>A	p.Val1239Met	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3715G>A	p.Val1239Met	missense_variant	1/1		NP_003595.1
IRS4	XM_011531061.2	c.3715G>A	p.Val1239Met	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4	c.3715G>A	p.Val1239Met	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.3715G>A	p.Val1239Met	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3715G>A	p.Val1239Met	missense_variant	1/1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098218 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363572

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

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

Oct 01, 2024

The c.3715G>A (p.V1239M) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a G to A substitution at nucleotide position 3715, causing the valine (V) at amino acid position 1239 to be replaced by a methionine (M). 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	0.22
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;N
REVEL	Benign	0.094
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.25	.;B
Vest4		0.35
MutPred		0.097		.;Loss of catalytic residue at D1242 (P = 0.1277);
MVP		0.41
MPC		0.50
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.16
gMVP		0.17

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-107975860;