chrX-108733268-G-A

Position:

• chrX-108733268-G-A

Variant summary

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

The NM_001379150.1(IRS4):​c.3077C>T​(p.Thr1026Ile) 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. 12/20 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: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

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=0.4211435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.3077C>T	p.Thr1026Ile	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.3077C>T	p.Thr1026Ile	missense_variant	1/1		NP_003595.1
IRS4	XM_011531061.2	c.3077C>T	p.Thr1026Ile	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4	c.3077C>T	p.Thr1026Ile	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.3077C>T	p.Thr1026Ile	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.3077C>T	p.Thr1026Ile	missense_variant	1/1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098211 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363565

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Jul 23, 2024

The c.3077C>T (p.T1026I) alteration is located in exon 1 (coding exon 1) of the IRS4 gene. This alteration results from a C to T substitution at nucleotide position 3077, causing the threonine (T) at amino acid position 1026 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.081
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.071	T
Polyphen		0.027	B
Vest4		0.075
MutPred		0.80		Gain of sheet (P = 0.0827);
MVP		0.093
MPC		0.53
ClinPred		0.49	T
GERP RS		3.4
Varity_R		0.22
gMVP		0.50

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-107976498;