rs1801164

Variant names:

• chrX-108733710-G-C
• rs1801164
• NM_001379150.1:c.2635C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-108733710-G-C
• chrX-108733710-G-A
• chrX-108733710-G-T

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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
• Publications: 31 publications found

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]

IRS4 Gene-Disease associations (from GenCC):

• hypothyroidism, congenital, nongoitrous, 9

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1284731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379150.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS4	NM_001379150.1	MANE Select	c.2635C>G	p.His879Asp	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
	IRS4	NM_001440817.1		c.2635C>G	p.His879Asp	missense	Exon 1 of 3	NP_001427746.1
	IRS4	NM_003604.2		c.2635C>G	p.His879Asp	missense	Exon 1 of 1	NP_003595.1	O14654

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS4	ENST00000372129.4	TSL:6 MANE Select	c.2635C>G	p.His879Asp	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.2635C>G	p.His879Asp	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes AF: 0.372 AC: 41049 AN: 110470 Hom.: 6999 Cov.: 22

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

GnomAD2 exomes AF: 0.361 AC: 66213 AN: 183438 AF XY: 0.340

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 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

African (AFR) AF: 0.631 AC: 16651 AN: 26399

American (AMR) AF: 0.636 AC: 22392 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 3659 AN: 19386

East Asian (EAS) AF: 0.692 AC: 20896 AN: 30206

South Asian (SAS) AF: 0.439 AC: 23759 AN: 54149

European-Finnish (FIN) AF: 0.153 AC: 6193 AN: 40529

Middle Eastern (MID) AF: 0.219 AC: 907 AN: 4137

European-Non Finnish (NFE) AF: 0.213 AC: 179624 AN: 842113

Other (OTH) AF: 0.295 AC: 13577 AN: 46097

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

African (AFR) AF: 0.628 AC: 18956 AN: 30208

American (AMR) AF: 0.516 AC: 5365 AN: 10398

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 477 AN: 2631

East Asian (EAS) AF: 0.670 AC: 2330 AN: 3478

South Asian (SAS) AF: 0.433 AC: 1124 AN: 2595

European-Finnish (FIN) AF: 0.140 AC: 830 AN: 5936

Middle Eastern (MID) AF: 0.190 AC: 41 AN: 216

European-Non Finnish (NFE) AF: 0.213 AC: 11238 AN: 52880

Other (OTH) AF: 0.357 AC: 541 AN: 1517

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Hypothyroidism, congenital, nongoitrous, 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.2
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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