X-108732873-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 12/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.657

Publications

3 publications found

Variant links:

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)

IRS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 VariationId is 713320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRS4	NM_001379150.1	MANE Select	c.3472G>A	p.Ala1158Thr	missense	Exon 1 of 2	NP_001366079.1	A0A804CF45
IRS4	NM_001440817.1		c.3472G>A	p.Ala1158Thr	missense	Exon 1 of 3	NP_001427746.1
IRS4	NM_003604.2		c.3472G>A	p.Ala1158Thr	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.3472G>A	p.Ala1158Thr	missense	Exon 1 of 2	ENSP00000361202.3	A0A804CF45
	IRS4	ENST00000564206.2	TSL:6	c.3472G>A	p.Ala1158Thr	missense	Exon 1 of 1	ENSP00000505547.1	O14654

Frequencies

GnomAD3 genomes

AF:

0.00667

AC:

749

AN:

112330

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00671

AC:

978

AN:

145752

AF XY:

0.00634

show subpopulations

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 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.:

Cov.:

AF XY:

0.00238

AC XY:

807

AN XY:

339237

show subpopulations

African (AFR)

AF:

0.0123

AC:

305

AN:

24794

American (AMR)

AF:

0.00140

AC:

AN:

29242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16689

East Asian (EAS)

AF:

0.0285

AC:

848

AN:

29759

South Asian (SAS)

AF:

0.0136

AC:

644

AN:

47441

European-Finnish (FIN)

AF:

0.0000523

AC:

AN:

38216

Middle Eastern (MID)

AF:

0.00152

AC:

AN:

3943

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

820744

Other (OTH)

AF:

0.00644

AC:

284

AN:

44113

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00670

AC:

753

AN:

112383

Hom.:

Cov.:

AF XY:

0.00671

AC XY:

232

AN XY:

34555

show subpopulations

African (AFR)

AF:

0.0153

AC:

474

AN:

30977

American (AMR)

AF:

0.00485

AC:

AN:

10723

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.0474

AC:

168

AN:

3545

South Asian (SAS)

AF:

0.0137

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6141

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

53227

Other (OTH)

AF:

0.00991

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00217

Hom.:

Bravo

AF:

0.00641

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.0139

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00617

AC:

743

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.66

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.54

REVEL

Benign

0.034

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.037

Polyphen

0.80

Vest4

0.062

MVP

0.33

MPC

0.48

ClinPred

0.014

GERP RS

3.8

Varity_R

0.13

gMVP

0.20

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over