X-108733163-G-A

Variant names:

• chrX-108733163-G-A
• rs755527863
• NM_001379150.1:c.3182C>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.3182C>T​(p.Ser1061Phe) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.608

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=0.16901758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3182C>T	p.Ser1061Phe	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3182C>T	p.Ser1061Phe	missense_variant	Exon 1 of 1		NP_003595.1
IRS4	XM_011531061.2	c.3182C>T	p.Ser1061Phe	missense_variant	Exon 1 of 3		XP_011529363.1
IRS4	XM_006724713.4	c.3182C>T	p.Ser1061Phe	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.3182C>T	p.Ser1061Phe	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3182C>T	p.Ser1061Phe	missense_variant	Exon 1 of 1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1097105 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 2 AN XY: 362545

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: 0.0000185

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	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.045
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.47	P
Vest4		0.14
MutPred		0.43		Loss of phosphorylation at S1061 (P = 0.0186);
MVP		0.21
MPC		0.54
ClinPred		0.46	T
GERP RS		3.6
Varity_R		0.28
gMVP		0.38

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: rs755527863; hg19: chrX-107976393;