rs17847227

Variant names:

• chrX-108732873-C-A
• NM_001379150.1:c.3472G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-108732873-C-A
• chrX-108732873-C-T

Variant summary

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

The NM_001379150.1(IRS4):​c.3472G>T​(p.Ala1158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000948 in 1,054,944 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: 9.5e-7 (0 hom. 0 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.657

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=0.32822698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3472G>T	p.Ala1158Ser	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3472G>T	p.Ala1158Ser	missense_variant	Exon 1 of 1		NP_003595.1
IRS4	XM_011531061.2	c.3472G>T	p.Ala1158Ser	missense_variant	Exon 1 of 3		XP_011529363.1
IRS4	XM_006724713.4	c.3472G>T	p.Ala1158Ser	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.3472G>T	p.Ala1158Ser	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3472G>T	p.Ala1158Ser	missense_variant	Exon 1 of 1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.48e-7 AC: 1 AN: 1054944 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 339238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000599

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.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.087
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.049	D
Polyphen		0.95	P
Vest4		0.22
MutPred		0.23		Gain of glycosylation at A1158 (P = 0.0335);
MVP		0.30
MPC		0.45
ClinPred		0.74	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.11

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-107976103;