X-108732669-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001379150.1(IRS4):c.3676C>A(p.Pro1226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,098,213 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 6 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06737661).
• BS2: High Hemizygotes in GnomAdExome at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS4	NM_001379150.1	c.3676C>A	p.Pro1226Thr	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2	c.3676C>A	p.Pro1226Thr	missense_variant	1/1
IRS4	XM_011531061.2	c.3676C>A	p.Pro1226Thr	missense_variant	1/3
IRS4	XM_006724713.4	c.3676C>A	p.Pro1226Thr	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4	c.3676C>A	p.Pro1226Thr	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2	c.3676C>A	p.Pro1226Thr	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.000136 AC: 25 AN: 183499 Hom.: 0 AF XY: 0.0000883 AC XY: 6 AN XY: 67941

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000912

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1098213 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 6 AN XY: 363571

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000710

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: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000378

ExAC AF: 0.0000741 AC: 9

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

Aug 17, 2022

The c.3676C>A (p.P1226T) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a C to A substitution at nucleotide position 3676, causing the proline (P) at amino acid position 1226 to be replaced by a threonine (T). 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	0.085
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.46	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.0	D;N
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.61	.;P
Vest4		0.14
MutPred		0.20		.;Gain of phosphorylation at P1226 (P = 0.0019);
MVP		0.24
MPC		0.55
ClinPred		0.27	T
GERP RS		3.5
Varity_R		0.14
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

LitVar

Other links and lift over

dbSNP: rs759723131; hg19: chrX-107975899; COSMIC: COSV64535677; COSMIC: COSV64535677;