dbSNP rs1801162: IRS4:p.Leu34Phe (chrX-108736245-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001379150.1(IRS4):c.100C>T(p.Leu34Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,208,866 control chromosomes in the GnomAD database, including 1,581 homozygotes. There are 23,175 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.061 ( 180 hom., 1875 hem., cov: 22)

Exomes 𝑓: 0.060 ( 1401 hom. 21300 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.356

Publications

12 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 links:

IRS4-AS1 (HGNC:55650): (IRS4 antisense RNA 1)

IRS4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014205873).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1 link	c.100C>T	p.Leu34Phe	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_001440817.1 link	c.100C>T	p.Leu34Phe	missense_variant	Exon 1 of 3		NP_001427746.1
IRS4	NM_003604.2 link	c.100C>T	p.Leu34Phe	missense_variant	Exon 1 of 1		NP_003595.1	O14654
IRS4	XM_006724713.4 link	c.100C>T	p.Leu34Phe	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.100C>T	p.Leu34Phe	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45

Frequencies

GnomAD3 genomes

AF:

0.0608

AC:

6770

AN:

111344

Hom.:

179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0696

Gnomad AMI

AF:

0.0150

Gnomad AMR

AF:

0.0784

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.000859

Gnomad SAS

AF:

0.0574

Gnomad FIN

AF:

0.0359

Gnomad MID

AF:

0.0598

Gnomad NFE

AF:

0.0603

Gnomad OTH

AF:

0.0710

GnomAD2 exomes

AF:

0.0557

AC:

10048

AN:

180245

AF XY:

0.0530

show subpopulations

Gnomad AFR exome

AF:

0.0727

Gnomad AMR exome

AF:

0.0854

Gnomad ASJ exome

AF:

0.0447

Gnomad EAS exome

AF:

0.000439

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0578

Gnomad OTH exome

AF:

0.0530

GnomAD4 exome

AF:

0.0596

AC:

65377

AN:

1097471

Hom.:

1401

Cov.:

AF XY:

0.0586

AC XY:

21300

AN XY:

363243

show subpopulations

African (AFR)

AF:

0.0701

AC:

1852

AN:

26401

American (AMR)

AF:

0.0826

AC:

2904

AN:

35173

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

821

AN:

19384

East Asian (EAS)

AF:

0.000199

AC:

AN:

30206

South Asian (SAS)

AF:

0.0584

AC:

3160

AN:

54144

European-Finnish (FIN)

AF:

0.0326

AC:

1299

AN:

39898

Middle Eastern (MID)

AF:

0.0596

AC:

246

AN:

4130

European-Non Finnish (NFE)

AF:

0.0623

AC:

52459

AN:

842048

Other (OTH)

AF:

0.0571

AC:

2630

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

2452

4904

7357

9809

12261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2030

4060

6090

8120

10150

<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:

0.0609

AC:

6784

AN:

111395

Hom.:

180

Cov.:

AF XY:

0.0558

AC XY:

1875

AN XY:

33629

show subpopulations

African (AFR)

AF:

0.0698

AC:

2144

AN:

30734

American (AMR)

AF:

0.0787

AC:

840

AN:

10671

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

114

AN:

2636

East Asian (EAS)

AF:

0.000861

AC:

AN:

3483

South Asian (SAS)

AF:

0.0583

AC:

154

AN:

2641

European-Finnish (FIN)

AF:

0.0359

AC:

216

AN:

6025

Middle Eastern (MID)

AF:

0.0708

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.0602

AC:

3182

AN:

52815

Other (OTH)

AF:

0.0701

AC:

106

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

239

478

716

955

1194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0593

Hom.:

2849

Bravo

AF:

0.0637

TwinsUK

AF:

0.0634

AC:

235

ALSPAC

AF:

0.0633

AC:

183

ESP6500AA

AF:

0.0668

AC:

256

ESP6500EA

AF:

0.0583

AC:

392

ExAC

AF:

0.0555

AC:

6736

EpiCase

AF:

0.0609

EpiControl

AF:

0.0601

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.95

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.36

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.44

REVEL

Benign

0.021

Sift

Benign

0.081

Sift4G

Benign

0.20

Polyphen

0.0020

Vest4

0.037

MPC

0.66

ClinPred

0.0036

GERP RS

0.36

PromoterAI

0.0070

Neutral

(source)

Varity_R

0.090

gMVP

0.26

Mutation Taster

=96/4

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

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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