rs80131334

Variant names:

• chrX-108735112-T-A
• rs80131334
• NM_001379150.1:c.1233A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-108735112-T-A
• chrX-108735112-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001379150.1(IRS4):​c.1233A>T​(p.Arg411Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,209,450 control chromosomes in the GnomAD database, including 1,525 homozygotes. There are 22,775 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.055 (149 hom., 1680 hem., cov: 22)
  • Exomes 𝑓: 0.059 (1376 hom. 21095 hem.)
• Consequence: IRS4 NM_001379150.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.435
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=0.435 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.1233A>T	p.Arg411Arg	synonymous_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_001440817.1	c.1233A>T	p.Arg411Arg	synonymous_variant	Exon 1 of 3		NP_001427746.1
IRS4	NM_003604.2	c.1233A>T	p.Arg411Arg	synonymous_variant	Exon 1 of 1		NP_003595.1
IRS4	XM_006724713.4	c.1233A>T	p.Arg411Arg	synonymous_variant	Exon 1 of 2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.1233A>T	p.Arg411Arg	synonymous_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.1233A>T	p.Arg411Arg	synonymous_variant	Exon 1 of 1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 6135 AN: 111404 Hom.: 148 Cov.: 22

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.0162

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.00113

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0638

Gnomad NFE AF: 0.0598

Gnomad OTH AF: 0.0676

GnomAD2 exomes AF: 0.0540 AC: 9871 AN: 182632 AF XY: 0.0515

Gnomad AFR exome AF: 0.0545

Gnomad AMR exome AF: 0.0838

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.000505

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0576

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0589 AC: 64701 AN: 1097991 Hom.: 1376 Cov.: 34 AF XY: 0.0581 AC XY: 21095 AN XY: 363383

African (AFR) AF: 0.0512 AC: 1352 AN: 26403

American (AMR) AF: 0.0815 AC: 2867 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 787 AN: 19385

East Asian (EAS) AF: 0.000199 AC: 6 AN: 30206

South Asian (SAS) AF: 0.0583 AC: 3155 AN: 54145

European-Finnish (FIN) AF: 0.0325 AC: 1311 AN: 40368

Middle Eastern (MID) AF: 0.0580 AC: 240 AN: 4137

European-Non Finnish (NFE) AF: 0.0623 AC: 52421 AN: 842075

Other (OTH) AF: 0.0556 AC: 2562 AN: 46097

GnomAD4 genome AF: 0.0551 AC: 6144 AN: 111459 Hom.: 149 Cov.: 22 AF XY: 0.0499 AC XY: 1680 AN XY: 33685

African (AFR) AF: 0.0507 AC: 1555 AN: 30672

American (AMR) AF: 0.0767 AC: 812 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 108 AN: 2640

East Asian (EAS) AF: 0.00114 AC: 4 AN: 3518

South Asian (SAS) AF: 0.0578 AC: 154 AN: 2664

European-Finnish (FIN) AF: 0.0362 AC: 217 AN: 5999

Middle Eastern (MID) AF: 0.0744 AC: 16 AN: 215

European-Non Finnish (NFE) AF: 0.0598 AC: 3167 AN: 52992

Other (OTH) AF: 0.0668 AC: 100 AN: 1498

Alfa AF: 0.0300 Hom.: 220

Bravo AF: 0.0575

EpiCase AF: 0.0608

EpiControl AF: 0.0590

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.1
DANN	Benign	0.80
PhyloP100		0.43
Mutation Taster		=100/0	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: rs80131334; hg19: chrX-107978342; COSMIC: COSV64535286; COSMIC: COSV64535286;