X-108735113-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001379150.1(IRS4):c.1232G>A(p.Arg411Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,209,567 control chromosomes in the GnomAD database, including 1,524 homozygotes. There are 22,779 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.055 ( 149 hom., 1681 hem., cov: 22)

Exomes 𝑓: 0.059 ( 1375 hom. 21098 hem. )

Consequence

IRS4
NM_001379150.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.0540

Publications

8 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016234219).

BP6

Variant X-108735113-C-T is Benign according to our data. Variant chrX-108735113-C-T is described in ClinVar as Benign. ClinVar VariationId is 1284757.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS4	NM_001379150.1 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_001440817.1 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 1 of 3		NP_001427746.1
IRS4	NM_003604.2 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 1 of 1		NP_003595.1	O14654
IRS4	XM_006724713.4 link	c.1232G>A	p.Arg411Gln	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.1232G>A	p.Arg411Gln	missense_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3		A0A804CF45
IRS4	ENST00000564206.2 link	c.1232G>A	p.Arg411Gln	missense_variant	Exon 1 of 1	6		ENSP00000505547.1		O14654

Frequencies

GnomAD3 genomes

AF:

0.0550

AC:

6137

AN:

111519

Hom.:

148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0507

Gnomad AMI

AF:

0.0161

Gnomad AMR

AF:

0.0766

Gnomad ASJ

AF:

0.0413

Gnomad EAS

AF:

0.00113

Gnomad SAS

AF:

0.0565

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0636

Gnomad NFE

AF:

0.0597

Gnomad OTH

AF:

0.0669

GnomAD2 exomes

AF:

0.0541

AC:

9874

AN:

182612

AF XY:

0.0515

show subpopulations

Gnomad AFR exome

AF:

0.0547

Gnomad AMR exome

AF:

0.0839

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.000577

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0576

Gnomad OTH exome

AF:

0.0522

GnomAD4 exome

AF:

0.0589

AC:

64707

AN:

1097994

Hom.:

1375

Cov.:

AF XY:

0.0581

AC XY:

21098

AN XY:

363384

show subpopulations

African (AFR)

AF:

0.0513

AC:

1354

AN:

26403

American (AMR)

AF:

0.0815

AC:

2866

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

787

AN:

19385

East Asian (EAS)

AF:

0.000232

AC:

AN:

30206

South Asian (SAS)

AF:

0.0583

AC:

3155

AN:

54144

European-Finnish (FIN)

AF:

0.0325

AC:

1312

AN:

40380

Middle Eastern (MID)

AF:

0.0580

AC:

240

AN:

4136

European-Non Finnish (NFE)

AF:

0.0623

AC:

52422

AN:

842069

Other (OTH)

AF:

0.0556

AC:

2564

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2928

5856

8783

11711

14639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2020

4040

6060

8080

10100

<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:

0.0551

AC:

6146

AN:

111573

Hom.:

149

Cov.:

AF XY:

0.0498

AC XY:

1681

AN XY:

33755

show subpopulations

African (AFR)

AF:

0.0507

AC:

1557

AN:

30718

American (AMR)

AF:

0.0769

AC:

813

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

109

AN:

2641

East Asian (EAS)

AF:

0.00114

AC:

AN:

3524

South Asian (SAS)

AF:

0.0574

AC:

154

AN:

2681

European-Finnish (FIN)

AF:

0.0360

AC:

216

AN:

5994

Middle Eastern (MID)

AF:

0.0741

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0597

AC:

3166

AN:

53026

Other (OTH)

AF:

0.0661

AC:

100

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

223

446

669

892

1115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0565

Hom.:

2596

Bravo

AF:

0.0575

TwinsUK

AF:

0.0634

AC:

235

ALSPAC

AF:

0.0640

AC:

185

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.00446

AC:

ExAC

AF:

0.0538

AC:

6536

EpiCase

AF:

0.0608

EpiControl

AF:

0.0591

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.9

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

PhyloP100

0.054

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.017

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0030

Polyphen

0.25

Vest4

0.036

MPC

0.62

ClinPred

0.0011

GERP RS

2.2

Varity_R

0.093

gMVP

0.28

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over