rs1799817

Positions:

chr19-7125286-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000208.4(INSR):c.3255C>T(p.His1085=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein
INSR	NM_000208.4 linkuse as main transcript	c.3255C>T	p.His1085=	synonymous_variant	17/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 linkuse as main transcript	c.3219C>T	p.His1073=	synonymous_variant	16/21		NP_001073285.1
INSR	XM_011527988.3 linkuse as main transcript	c.3252C>T	p.His1084=	synonymous_variant	17/22		XP_011526290.2
INSR	XM_011527989.4 linkuse as main transcript	c.3216C>T	p.His1072=	synonymous_variant	16/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10 linkuse as main transcript	c.3255C>T	p.His1085=	synonymous_variant	17/22	1	NM_000208.4	ENSP00000303830	A2	P06213-1
INSR	ENST00000341500.9 linkuse as main transcript	c.3219C>T	p.His1073=	synonymous_variant	16/21	1		ENSP00000342838	P3	P06213-2
INSR	ENST00000593970.1 linkuse as main transcript	n.101C>T		non_coding_transcript_exon_variant	1/3	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

GnomAD3 exomes

AF:

0.227

AC:

56640

AN:

249496

Hom.:

7156

AF XY:

0.228

AC XY:

30756

AN XY:

134932

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 SAS exome

AF:

0.312

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

Gnomad4 AFR exome

AF:

0.227

Gnomad4 AMR exome

AF:

0.252

Gnomad4 ASJ exome

AF:

0.149

Gnomad4 EAS exome

AF:

0.369

Gnomad4 SAS exome

AF:

0.313

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.182

Gnomad4 OTH exome

AF:

0.214

GnomAD4 genome

AF:

0.209

AC:

31836

AN:

151988

Hom.:

3547

Cov.:

AF XY:

0.212

AC XY:

15718

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.229

Gnomad4 AMR

AF:

0.227

Gnomad4 ASJ

AF:

0.157

Gnomad4 EAS

AF:

0.402

Gnomad4 SAS

AF:

0.323

Gnomad4 FIN

AF:

0.183

Gnomad4 NFE

AF:

0.179

Gnomad4 OTH

AF:

0.206

Alfa

AF:

0.188

Hom.:

5353

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 19211708, 19926323, 22775283) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 08, 2015

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

DANN

Benign

0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over