dbSNP rs2073114: IRS4:p.Ala21Ala (chrX-108736282-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001379150.1(IRS4):c.63G>A(p.Ala21Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,202,303 control chromosomes in the GnomAD database, including 39,372 homozygotes. There are 102,411 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 7404 hom., 11748 hem., cov: 22)

Exomes 𝑓: 0.26 ( 31968 hom. 90663 hem. )

Consequence

IRS4
NM_001379150.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.671

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 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant X-108736282-C-T is Benign according to our data. Variant chrX-108736282-C-T is described in ClinVar as Benign. ClinVar VariationId is 1300045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.671 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IRS4	NM_001379150.1 link	c.63G>A	p.Ala21Ala	synonymous_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_001440817.1 link	c.63G>A	p.Ala21Ala	synonymous_variant	Exon 1 of 3		NP_001427746.1
IRS4	NM_003604.2 link	c.63G>A	p.Ala21Ala	synonymous_variant	Exon 1 of 1		NP_003595.1
IRS4	XM_006724713.4 link	c.63G>A	p.Ala21Ala	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 link	c.63G>A	p.Ala21Ala	synonymous_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

41439

AN:

109883

Hom.:

7401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.656

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.515

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.662

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.162

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.360

GnomAD2 exomes

AF:

0.346

AC:

61225

AN:

176758

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.653

Gnomad AMR exome

AF:

0.641

Gnomad ASJ exome

AF:

0.181

Gnomad EAS exome

AF:

0.642

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.283

GnomAD4 exome

AF:

0.258

AC:

282352

AN:

1092370

Hom.:

31968

Cov.:

AF XY:

0.253

AC XY:

90663

AN XY:

358512

show subpopulations

African (AFR)

AF:

0.657

AC:

17213

AN:

26200

American (AMR)

AF:

0.632

AC:

21930

AN:

34717

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

3609

AN:

19334

East Asian (EAS)

AF:

0.686

AC:

20463

AN:

29808

South Asian (SAS)

AF:

0.418

AC:

22371

AN:

53486

European-Finnish (FIN)

AF:

0.150

AC:

5997

AN:

39929

Middle Eastern (MID)

AF:

0.217

AC:

889

AN:

4098

European-Non Finnish (NFE)

AF:

0.210

AC:

176489

AN:

838940

Other (OTH)

AF:

0.292

AC:

13391

AN:

45858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

7826

15652

23477

31303

39129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7008

14016

21024

28032

35040

<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:

0.377

AC:

41499

AN:

109933

Hom.:

7404

Cov.:

AF XY:

0.363

AC XY:

11748

AN XY:

32373

show subpopulations

African (AFR)

AF:

0.656

AC:

19690

AN:

30003

American (AMR)

AF:

0.515

AC:

5371

AN:

10427

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

475

AN:

2627

East Asian (EAS)

AF:

0.662

AC:

2213

AN:

3343

South Asian (SAS)

AF:

0.418

AC:

1075

AN:

2574

European-Finnish (FIN)

AF:

0.137

AC:

812

AN:

5924

Middle Eastern (MID)

AF:

0.187

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.210

AC:

11082

AN:

52675

Other (OTH)

AF:

0.358

AC:

534

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

743

1486

2229

2972

3715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.273

Hom.:

2622

Bravo

AF:

0.422

EpiCase

AF:

0.209

EpiControl

AF:

0.200

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypothyroidism, congenital, nongoitrous, 9

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.0

(source)

DANN

Benign

0.95

PhyloP100

-0.67

PromoterAI

0.0047

Neutral

(source)

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

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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