X-108732873-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001379150.1(IRS4):c.3472G>A(p.Ala1158Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,167,324 control chromosomes in the GnomAD database, including 32 homozygotes. There are 1,039 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (9 hom., 232 hem., cov: 23)
  • Exomes 𝑓: 0.0021 (23 hom. 807 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033047497).
• BP6: Variant X-108732873-C-T is Benign according to our data. Variant chrX-108732873-C-T is described in ClinVar as [Benign]. Clinvar id is 713320.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108732873-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0067 (753/112383) while in subpopulation EAS AF= 0.0474 (168/3545). AF 95% confidence interval is 0.0415. There are 9 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS4	NM_001379150.1	c.3472G>A	p.Ala1158Thr	missense_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2	c.3472G>A	p.Ala1158Thr	missense_variant	1/1
IRS4	XM_011531061.2	c.3472G>A	p.Ala1158Thr	missense_variant	1/3
IRS4	XM_006724713.4	c.3472G>A	p.Ala1158Thr	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4	c.3472G>A	p.Ala1158Thr	missense_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2	c.3472G>A	p.Ala1158Thr	missense_variant	1/1			P5

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 749 AN: 112330 Hom.: 9 Cov.: 23 AF XY: 0.00673 AC XY: 232 AN XY: 34492

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00486

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.0140

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.00736

GnomAD3 exomes AF: 0.00671 AC: 978 AN: 145752 Hom.: 17 AF XY: 0.00634 AC XY: 301 AN XY: 47496

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0457

Gnomad SAS exome AF: 0.0185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000295

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00205 AC: 2167 AN: 1054941 Hom.: 23 Cov.: 31 AF XY: 0.00238 AC XY: 807 AN XY: 339237

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0285

Gnomad4 SAS exome AF: 0.0136

Gnomad4 FIN exome AF: 0.0000523

Gnomad4 NFE exome AF: 0.0000451

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00670 AC: 753 AN: 112383 Hom.: 9 Cov.: 23 AF XY: 0.00671 AC XY: 232 AN XY: 34555

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.00485

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0474

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00991

Alfa AF: 0.00118 Hom.: 45

Bravo AF: 0.00641

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.0139 AC: 53

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00617 AC: 743

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.034
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.037	D
Polyphen		0.80	P
Vest4		0.062
MVP		0.33
MPC		0.48
ClinPred		0.014	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.20

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: rs17847227; hg19: chrX-107976103; COSMIC: COSV64532689; COSMIC: COSV64532689;