rs1799817

Variant names:

• chr19-7125286-G-A
• rs1799817
• NM_000208.4:c.3255C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.971

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]

ACMG classification

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 rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.3255C>T	p.His1085His	synonymous_variant	Exon 17 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.3219C>T	p.His1073His	synonymous_variant	Exon 16 of 21		NP_001073285.1
INSR	XM_011527988.3	c.3252C>T	p.His1084His	synonymous_variant	Exon 17 of 22		XP_011526290.2
INSR	XM_011527989.4	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	Appris	UniProt
INSR	ENST00000302850.10	c.3255C>T	p.His1085His	synonymous_variant	Exon 17 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.3219C>T	p.His1073His	synonymous_variant	Exon 16 of 21	1		ENSP00000342838.4
INSR	ENST00000593970.1	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.: 30

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

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.: 35 AF XY: 0.202 AC XY: 146547 AN XY: 727134

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.: 30 AF XY: 0.212 AC XY: 15718 AN XY: 74274

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

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) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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
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

Other links and lift over

dbSNP: rs1799817; hg19: chr19-7125297; COSMIC: COSV57158382; COSMIC: COSV57158382;