X-108733269-T-C

Position:

• chrX-108733269-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001379150.1(IRS4):​c.3076A>G​(p.Thr1026Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,098,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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: 0.000020 (0 hom. 5 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.939

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23148036).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3076A>G	p.Thr1026Ala	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3076A>G	p.Thr1026Ala	missense_variant	1/1		NP_003595.1
IRS4	XM_011531061.2	c.3076A>G	p.Thr1026Ala	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4	c.3076A>G	p.Thr1026Ala	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.3076A>G	p.Thr1026Ala	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3076A>G	p.Thr1026Ala	missense_variant	1/1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000272 AC: 5 AN: 183507 Hom.: 0 AF XY: 0.0000442 AC XY: 3 AN XY: 67935

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000366

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.0000200 AC: 22 AN: 1098148 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 5 AN XY: 363506

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: 0.0000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000556 Hom.: 2

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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 25, 2024

The c.3076A>G (p.T1026A) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a A to G substitution at nucleotide position 3076, causing the threonine (T) at amino acid position 1026 to be replaced by an alanine (A). 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	0.087
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.059
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.012	B
Vest4		0.034
MutPred		0.74		Loss of loop (P = 0.0112);
MVP		0.093
MPC		0.48
ClinPred		0.020	T
GERP RS		1.4
Varity_R		0.18
gMVP		0.39

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: rs750128009; hg19: chrX-107976499;