19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGAGAGAGA

Variant names:

• chr19-7184640-G-GGAGA
• rs3835070
• NM_000208.4:c.653-7_653-4dupTCTC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000208.4(INSR):​c.653-7_653-4dupTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.044 (264 hom., cov: 0)
  • Exomes 𝑓: 0.0099 (135 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -2.04
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 19-7184640-G-GGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330477.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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.653-7_653-4dupTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-7_653-4dupTCTC		splice_region intron	N/A	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.653-4_653-3insTCTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTCTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTCTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6228 AN: 142148 Hom.: 263 Cov.: 0

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000400

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.00382

Gnomad MID AF: 0.0592

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0169 AC: 2329 AN: 137742 AF XY: 0.0181

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00801

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.000399

Gnomad FIN exome AF: 0.00313

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00986 AC: 12158 AN: 1233004 Hom.: 135 Cov.: 17 AF XY: 0.0105 AC XY: 6490 AN XY: 617394

African (AFR) AF: 0.0610 AC: 1511 AN: 24762

American (AMR) AF: 0.00880 AC: 348 AN: 39530

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 425 AN: 23084

East Asian (EAS) AF: 0.000302 AC: 11 AN: 36478

South Asian (SAS) AF: 0.0181 AC: 1274 AN: 70400

European-Finnish (FIN) AF: 0.00330 AC: 156 AN: 47238

Middle Eastern (MID) AF: 0.0225 AC: 88 AN: 3914

European-Non Finnish (NFE) AF: 0.00814 AC: 7623 AN: 936500

Other (OTH) AF: 0.0141 AC: 722 AN: 51098

GnomAD4 genome AF: 0.0439 AC: 6240 AN: 142238 Hom.: 264 Cov.: 0 AF XY: 0.0430 AC XY: 2968 AN XY: 68970

African (AFR) AF: 0.112 AC: 4066 AN: 36330

American (AMR) AF: 0.0258 AC: 368 AN: 14274

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 90 AN: 3398

East Asian (EAS) AF: 0.000401 AC: 2 AN: 4986

South Asian (SAS) AF: 0.0334 AC: 150 AN: 4494

European-Finnish (FIN) AF: 0.00382 AC: 36 AN: 9414

Middle Eastern (MID) AF: 0.0674 AC: 19 AN: 282

European-Non Finnish (NFE) AF: 0.0214 AC: 1417 AN: 66242

Other (OTH) AF: 0.0474 AC: 92 AN: 1942

Alfa AF: 0.0109 Hom.: 141

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Apr 09, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Insulin-resistant diabetes mellitus AND acanthosis nigricans Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rabson-Mendenhall syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leprechaunism syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

May 14, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3835070; hg19: chr19-7184651;