dbSNP rs73253702: IRS4:p.Thr46Thr (chrX-108736207-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001379150.1(IRS4):c.138C>T(p.Thr46Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,208,224 control chromosomes in the GnomAD database, including 1,589 homozygotes. There are 23,214 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.062 ( 182 hom., 1892 hem., cov: 21)

Exomes 𝑓: 0.060 ( 1407 hom. 21322 hem. )

Consequence

IRS4
NM_001379150.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

6 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP7

Synonymous conserved (PhyloP=1.52 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IRS4	NM_001379150.1 link	c.138C>T	p.Thr46Thr	synonymous_variant	Exon 1 of 2	ENST00000372129.4	NP_001366079.1
IRS4	NM_001440817.1 link	c.138C>T	p.Thr46Thr	synonymous_variant	Exon 1 of 3		NP_001427746.1
IRS4	NM_003604.2 link	c.138C>T	p.Thr46Thr	synonymous_variant	Exon 1 of 1		NP_003595.1
IRS4	XM_006724713.4 link	c.138C>T	p.Thr46Thr	synonymous_variant	Exon 1 of 2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IRS4	ENST00000372129.4 link	c.138C>T	p.Thr46Thr	synonymous_variant	Exon 1 of 2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2 link	c.138C>T	p.Thr46Thr	synonymous_variant	Exon 1 of 1	6		ENSP00000505547.1
IRS4-AS1	ENST00000608811.1 link	n.197G>A		non_coding_transcript_exon_variant	Exon 1 of 2	4
IRS4-AS1	ENST00000668534.2 link	n.199G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0616

AC:

6833

AN:

110991

Hom.:

181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0720

Gnomad AMI

AF:

0.0149

Gnomad AMR

AF:

0.0784

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0569

Gnomad FIN

AF:

0.0365

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0605

Gnomad OTH

AF:

0.0699

GnomAD2 exomes

AF:

0.0562

AC:

10106

AN:

179974

AF XY:

0.0536

show subpopulations

Gnomad AFR exome

AF:

0.0754

Gnomad AMR exome

AF:

0.0860

Gnomad ASJ exome

AF:

0.0446

Gnomad EAS exome

AF:

0.000510

Gnomad FIN exome

AF:

0.0305

Gnomad NFE exome

AF:

0.0581

Gnomad OTH exome

AF:

0.0535

GnomAD4 exome

AF:

0.0597

AC:

65480

AN:

1097184

Hom.:

1407

Cov.:

AF XY:

0.0587

AC XY:

21322

AN XY:

363058

show subpopulations

African (AFR)

AF:

0.0735

AC:

1939

AN:

26398

American (AMR)

AF:

0.0831

AC:

2923

AN:

35181

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

821

AN:

19382

East Asian (EAS)

AF:

0.000199

AC:

AN:

30203

South Asian (SAS)

AF:

0.0584

AC:

3164

AN:

54137

European-Finnish (FIN)

AF:

0.0325

AC:

1291

AN:

39781

Middle Eastern (MID)

AF:

0.0598

AC:

247

AN:

4130

European-Non Finnish (NFE)

AF:

0.0623

AC:

52445

AN:

841891

Other (OTH)

AF:

0.0574

AC:

2644

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

2196

4392

6589

8785

10981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2032

4064

6096

8128

10160

<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:

0.0617

AC:

6847

AN:

111040

Hom.:

182

Cov.:

AF XY:

0.0568

AC XY:

1892

AN XY:

33312

show subpopulations

African (AFR)

AF:

0.0721

AC:

2209

AN:

30622

American (AMR)

AF:

0.0787

AC:

836

AN:

10629

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

114

AN:

2639

East Asian (EAS)

AF:

0.00116

AC:

AN:

3456

South Asian (SAS)

AF:

0.0578

AC:

152

AN:

2628

European-Finnish (FIN)

AF:

0.0365

AC:

218

AN:

5969

Middle Eastern (MID)

AF:

0.0711

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.0604

AC:

3185

AN:

52706

Other (OTH)

AF:

0.0690

AC:

104

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

239

478

718

957

1196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0369

Hom.:

241

Bravo

AF:

0.0645

EpiCase

AF:

0.0609

EpiControl

AF:

0.0608

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

1.5

PromoterAI

-0.034

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

Computational scores

Splicing

Publications

Other links and lift over