dbSNP rs137853896: IRS4:p.Ser439Cys (chrX-108735030-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001379150.1(IRS4):c.1315A>T(p.Ser439Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,210,186 control chromosomes in the GnomAD database, including 3 homozygotes. There are 295 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., 23 hem., cov: 22)

Exomes 𝑓: 0.00073 ( 3 hom. 272 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.228

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005941719).

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1 link	c.1315A>T	p.Ser439Cys	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_001440817.1 link	c.1315A>T	p.Ser439Cys	missense_variant	Exon 1 of 3		NP_001427746.1
IRS4	NM_003604.2 link	c.1315A>T	p.Ser439Cys	missense_variant	Exon 1 of 1		NP_003595.1	O14654
IRS4	XM_006724713.4 link	c.1315A>T	p.Ser439Cys	missense_variant	Exon 1 of 2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4 link	c.1315A>T	p.Ser439Cys	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 link	c.1315A>T	p.Ser439Cys	missense_variant	Exon 1 of 1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.000608

AC:

AN:

111899

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000739

Gnomad FIN

AF:

0.00446

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000640

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00111

AC:

203

AN:

183389

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00638

Gnomad NFE exome

AF:

0.000904

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.000732

AC:

804

AN:

1098232

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

272

AN XY:

363590

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26403

American (AMR)

AF:

0.0000284

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00102

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00632

AC:

256

AN:

40498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000555

AC:

467

AN:

842148

Other (OTH)

AF:

0.000477

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000607

AC:

AN:

111954

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

34148

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30822

American (AMR)

AF:

0.00

AC:

AN:

10630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.000740

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00446

AC:

AN:

6048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000640

AC:

AN:

53131

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000582

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.00112

AC:

136

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Uncertain

0.60

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.37

M_CAP

Benign

0.0089

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

-0.23

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.019

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.0070

Vest4

0.040

MVP

0.068

MPC

0.58

ClinPred

0.022

GERP RS

-0.42

Varity_R

0.17

gMVP

0.64

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over