X-108733710-G-C

Position:

• chrX-108733710-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379150.1(IRS4):​c.2635C>G​(p.His879Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,208,751 control chromosomes in the GnomAD database, including 39,096 homozygotes. There are 107,587 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (7003 hom., 11956 hem., cov: 22)
  • Exomes 𝑓: 0.26 (32093 hom. 95631 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.0510345E-6).
• BP6: Variant X-108733710-G-C is Benign according to our data. Variant chrX-108733710-G-C is described in ClinVar as [Benign]. Clinvar id is 1284731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108733710-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.2635C>G	p.His879Asp	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.2635C>G	p.His879Asp	missense_variant	1/1		NP_003595.1
IRS4	XM_011531061.2	c.2635C>G	p.His879Asp	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4	c.2635C>G	p.His879Asp	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.2635C>G	p.His879Asp	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.2635C>G	p.His879Asp	missense_variant	1/1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 41049 AN: 110470 Hom.: 6999 Cov.: 22 AF XY: 0.363 AC XY: 11902 AN XY: 32750

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.361 AC: 66213 AN: 183438 Hom.: 10929 AF XY: 0.340 AC XY: 23063 AN XY: 67898

Gnomad AFR exome AF: 0.632

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.661

Gnomad SAS exome AF: 0.452

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.262 AC: 287658 AN: 1098223 Hom.: 32093 Cov.: 34 AF XY: 0.263 AC XY: 95631 AN XY: 363591

Gnomad4 AFR exome AF: 0.631

Gnomad4 AMR exome AF: 0.636

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.692

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.153

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.295

GnomAD4 genome AF: 0.372 AC: 41112 AN: 110528 Hom.: 7003 Cov.: 22 AF XY: 0.364 AC XY: 11956 AN XY: 32818

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.357

Alfa AF: 0.216 Hom.: 5708

Bravo AF: 0.412

TwinsUK AF: 0.219 AC: 812

ALSPAC AF: 0.214 AC: 618

ESP6500AA AF: 0.614 AC: 2353

ESP6500EA AF: 0.210 AC: 1412

ExAC AF: 0.350 AC: 42540

EpiCase AF: 0.211

EpiControl AF: 0.216

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hypothyroidism, congenital, nongoitrous, 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.99	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.32
DANN	Benign	0.45
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.68
ClinPred		0.00095	T
GERP RS		4.2
Varity_R		0.053
gMVP		0.065

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: rs1801164; hg19: chrX-107976940; COSMIC: COSV64533063; COSMIC: COSV64533063;