rs1799815

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000208.4(INSR):c.3033C>T(p.Tyr1011Tyr) 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 1,613,762 control chromosomes in the GnomAD database, including 3,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 222 hom., cov: 31)

Exomes 𝑓: 0.061 ( 3187 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.587

Publications

19 publications found

Variant links:

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

insulin-resistance syndrome type A
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
Donohue syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
hyperinsulinism due to INSR deficiency
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
Rabson-Mendenhall syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

INSR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 19-7125508-G-A is Benign according to our data. Variant chr19-7125508-G-A is described in ClinVar as Benign. ClinVar VariationId is 330447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.587 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0661 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.3033C>T	p.Tyr1011Tyr	synonymous	Exon 17 of 22	NP_000199.2
	INSR	NM_001079817.3		c.2997C>T	p.Tyr999Tyr	synonymous	Exon 16 of 21	NP_001073285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INSR	ENST00000302850.10	TSL:1 MANE Select	c.3033C>T	p.Tyr1011Tyr	synonymous	Exon 17 of 22	ENSP00000303830.4
INSR	ENST00000341500.9	TSL:1	c.2997C>T	p.Tyr999Tyr	synonymous	Exon 16 of 21	ENSP00000342838.4
INSR	ENST00000593970.1	TSL:2	n.-122C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0464

AC:

7056

AN:

152126

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0403

Gnomad ASJ

AF:

0.0827

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.0720

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0678

Gnomad OTH

AF:

0.0617

GnomAD2 exomes

AF:

0.0505

AC:

12672

AN:

251024

AF XY:

0.0517

show subpopulations

Gnomad AFR exome

AF:

0.00978

Gnomad AMR exome

AF:

0.0379

Gnomad ASJ exome

AF:

0.0800

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0717

Gnomad NFE exome

AF:

0.0695

Gnomad OTH exome

AF:

0.0640

GnomAD4 exome

AF:

0.0613

AC:

89639

AN:

1461518

Hom.:

3187

Cov.:

AF XY:

0.0605

AC XY:

43964

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.0117

AC:

391

AN:

33478

American (AMR)

AF:

0.0395

AC:

1768

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0792

AC:

2070

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0196

AC:

1689

AN:

86256

European-Finnish (FIN)

AF:

0.0708

AC:

3762

AN:

53104

Middle Eastern (MID)

AF:

0.0962

AC:

555

AN:

5768

European-Non Finnish (NFE)

AF:

0.0683

AC:

75921

AN:

1111962

Other (OTH)

AF:

0.0576

AC:

3479

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

4971

9942

14912

19883

24854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2750

5500

8250

11000

13750

<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:

0.0463

AC:

7052

AN:

152244

Hom.:

222

Cov.:

AF XY:

0.0467

AC XY:

3474

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0115

AC:

477

AN:

41538

American (AMR)

AF:

0.0402

AC:

615

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0827

AC:

287

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0165

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0720

AC:

763

AN:

10598

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0678

AC:

4609

AN:

68008

Other (OTH)

AF:

0.0615

AC:

130

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

349

698

1047

1396

1745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0591

Hom.:

388

Bravo

AF:

0.0431

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0722

EpiControl

AF:

0.0760

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)

Leprechaunism syndrome (1)

not specified (1)

Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.5

(source)

DANN

Benign

0.48

PhyloP100

-0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over