X-108732657-C-T

Variant names:

• chrX-108732657-C-T
• rs28546943
• NM_001379150.1:c.3688G>A

Variant summary

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

The NM_001379150.1(IRS4):​c.3688G>A​(p.Asp1230Asn) 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 1,098,240 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1230Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.830

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=0.13055342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3688G>A	p.Asp1230Asn	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3688G>A	p.Asp1230Asn	missense_variant	Exon 1 of 1		NP_003595.1
IRS4	XM_011531061.2	c.3688G>A	p.Asp1230Asn	missense_variant	Exon 1 of 3		XP_011529363.1
IRS4	XM_006724713.4	c.3688G>A	p.Asp1230Asn	missense_variant	Exon 1 of 2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.3688G>A	p.Asp1230Asn	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3688G>A	p.Asp1230Asn	missense_variant	Exon 1 of 1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098240 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363596

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D;N
REVEL	Benign	0.12
Sift	Benign	0.61	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.74	.;P
Vest4		0.093
MutPred		0.071		.;Gain of relative solvent accessibility (P = 0.0479);
MVP		0.35
MPC		0.48
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.089
gMVP		0.071

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

Other links and lift over

dbSNP: rs28546943; hg19: chrX-107975887;