chr19-7184640-G-GGA

Variant names:

• chr19-7184640-G-GGA
• rs3835070
• NM_000208.4:c.653-5_653-4dupTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.653-5_653-4dupTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3144 hom., cov: 0)
  • Exomes 𝑓: 0.059 (2044 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• 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 -16 ACMG points.

• BP6: Variant 19-7184640-G-GGA is Benign according to our data. Variant chr19-7184640-G-GGA is described in ClinVar as Benign. ClinVar VariationId is 211197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 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.653-5_653-4dupTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-5_653-4dupTC		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_653-3insTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.166 AC: 23605 AN: 142072 Hom.: 3130 Cov.: 0

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0552

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.0869 AC: 11968 AN: 137742 AF XY: 0.0904

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.0497

Gnomad ASJ exome AF: 0.0507

Gnomad EAS exome AF: 0.0640

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.0708

Gnomad OTH exome AF: 0.0849

GnomAD4 exome AF: 0.0594 AC: 73069 AN: 1230184 Hom.: 2044 Cov.: 17 AF XY: 0.0625 AC XY: 38474 AN XY: 615936

African (AFR) AF: 0.223 AC: 5510 AN: 24666

American (AMR) AF: 0.0508 AC: 2004 AN: 39446

Ashkenazi Jewish (ASJ) AF: 0.0428 AC: 984 AN: 23012

East Asian (EAS) AF: 0.0659 AC: 2393 AN: 36288

South Asian (SAS) AF: 0.124 AC: 8695 AN: 70238

European-Finnish (FIN) AF: 0.0638 AC: 2999 AN: 46998

Middle Eastern (MID) AF: 0.0786 AC: 307 AN: 3908

European-Non Finnish (NFE) AF: 0.0495 AC: 46271 AN: 934666

Other (OTH) AF: 0.0766 AC: 3906 AN: 50962

GnomAD4 genome AF: 0.166 AC: 23652 AN: 142160 Hom.: 3144 Cov.: 0 AF XY: 0.165 AC XY: 11341 AN XY: 68934

African (AFR) AF: 0.374 AC: 13544 AN: 36254

American (AMR) AF: 0.102 AC: 1460 AN: 14276

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 188 AN: 3404

East Asian (EAS) AF: 0.0799 AC: 398 AN: 4984

South Asian (SAS) AF: 0.182 AC: 818 AN: 4492

European-Finnish (FIN) AF: 0.0725 AC: 682 AN: 9408

Middle Eastern (MID) AF: 0.113 AC: 32 AN: 282

European-Non Finnish (NFE) AF: 0.0916 AC: 6067 AN: 66248

Other (OTH) AF: 0.151 AC: 292 AN: 1940

Alfa AF: 0.0472 Hom.: 141

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Nov 18, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 2017

Eurofins Ntd Llc (ga)

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 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rabson-Mendenhall syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leprechaunism syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=97/3	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;