rs1799817

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.3255C>T(p.His1085His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,618 control chromosomes in the GnomAD database, including 34,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3547 hom., cov: 30)

Exomes 𝑓: 0.20 ( 30522 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.971

Publications

85 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=-0.74).

BP6

Variant 19-7125286-G-A is Benign according to our data. Variant chr19-7125286-G-A is described in ClinVar as Benign. ClinVar VariationId is 194701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.971 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
INSR	NM_000208.4 link	c.3255C>T	p.His1085His	synonymous_variant	Exon 17 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 link	c.3219C>T	p.His1073His	synonymous_variant	Exon 16 of 21		NP_001073285.1
INSR	XM_011527988.3 link	c.3252C>T	p.His1084His	synonymous_variant	Exon 17 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.3216C>T	p.His1072His	synonymous_variant	Exon 16 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
INSR	ENST00000302850.10 link	c.3255C>T	p.His1085His	synonymous_variant	Exon 17 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9 link	c.3219C>T	p.His1073His	synonymous_variant	Exon 16 of 21	1		ENSP00000342838.4
INSR	ENST00000593970.1 link	n.101C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31790

AN:

151870

Hom.:

3538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.401

Gnomad SAS

AF:

0.324

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.179

Gnomad OTH

AF:

0.203

GnomAD2 exomes

AF:

0.227

AC:

56640

AN:

249496

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.230

Gnomad AMR exome

AF:

0.246

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.199

AC:

290172

AN:

1461630

Hom.:

30522

Cov.:

AF XY:

0.202

AC XY:

146547

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.227

AC:

7595

AN:

33476

American (AMR)

AF:

0.252

AC:

11250

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3885

AN:

26136

East Asian (EAS)

AF:

0.369

AC:

14654

AN:

39696

South Asian (SAS)

AF:

0.313

AC:

26954

AN:

86252

European-Finnish (FIN)

AF:

0.184

AC:

9790

AN:

53274

Middle Eastern (MID)

AF:

0.227

AC:

1308

AN:

5752

European-Non Finnish (NFE)

AF:

0.182

AC:

201824

AN:

1111938

Other (OTH)

AF:

0.214

AC:

12912

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

14919

29838

44756

59675

74594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7396

14792

22188

29584

36980

<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:

0.209

AC:

31836

AN:

151988

Hom.:

3547

Cov.:

AF XY:

0.212

AC XY:

15718

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.229

AC:

9487

AN:

41446

American (AMR)

AF:

0.227

AC:

3472

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

545

AN:

3466

East Asian (EAS)

AF:

0.402

AC:

2062

AN:

5134

South Asian (SAS)

AF:

0.323

AC:

1555

AN:

4812

European-Finnish (FIN)

AF:

0.183

AC:

1939

AN:

10582

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.179

AC:

12158

AN:

67970

Other (OTH)

AF:

0.206

AC:

434

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1278

2556

3834

5112

6390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<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:

0.193

Hom.:

11993

Bravo

AF:

0.214

Asia WGS

AF:

0.352

AC:

1222

AN:

3478

EpiCase

AF:

0.180

EpiControl

AF:

0.185

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19211708, 19926323, 22775283) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

May 08, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Rabson-Mendenhall syndrome

Benign:1

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Leprechaunism syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.34

(source)

DANN

Benign

0.44

PhyloP100

-0.97

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)

0.010

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