19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr19-7184640-G-GGAGAGAGA
• rs3835070
• NM_000208.4:c.653-11_653-4dupTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000208.4(INSR):​c.653-11_653-4dupTCTCTCTC 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 0.0058 (9 hom., cov: 0)
  • Exomes 𝑓: 0.00050 (8 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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-GGAGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGAGA is described in ClinVar as Benign. ClinVar VariationId is 780508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00581 (827/142242) while in subpopulation EAS AF = 0.0199 (99/4982). AF 95% confidence interval is 0.0177. There are 9 homozygotes in GnomAd4. There are 391 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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.653-11_653-4dupTCTCTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-11_653-4dupTCTCTCTC		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_653-3insTCTCTCTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTCTCTCTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTCTCTCTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 824 AN: 142152 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00182

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.00312

GnomAD2 exomes AF: 0.00118 AC: 163 AN: 137742 AF XY: 0.00106

Gnomad AFR exome AF: 0.00815

Gnomad AMR exome AF: 0.000507

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.00769

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.000578

GnomAD4 exome AF: 0.000499 AC: 616 AN: 1233768 Hom.: 8 Cov.: 17 AF XY: 0.000476 AC XY: 294 AN XY: 617872

African (AFR) AF: 0.00768 AC: 190 AN: 24746

American (AMR) AF: 0.000657 AC: 26 AN: 39554

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 26 AN: 23120

East Asian (EAS) AF: 0.00722 AC: 263 AN: 36436

South Asian (SAS) AF: 0.000170 AC: 12 AN: 70474

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47250

Middle Eastern (MID) AF: 0.00128 AC: 5 AN: 3920

European-Non Finnish (NFE) AF: 0.0000405 AC: 38 AN: 937134

Other (OTH) AF: 0.00108 AC: 55 AN: 51134

GnomAD4 genome AF: 0.00581 AC: 827 AN: 142242 Hom.: 9 Cov.: 0 AF XY: 0.00567 AC XY: 391 AN XY: 68970

African (AFR) AF: 0.0188 AC: 683 AN: 36268

American (AMR) AF: 0.00182 AC: 26 AN: 14292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.0199 AC: 99 AN: 4982

South Asian (SAS) AF: 0.000222 AC: 1 AN: 4496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000181 AC: 12 AN: 66284

Other (OTH) AF: 0.00309 AC: 6 AN: 1942

Alfa AF: 0.000242 Hom.: 141

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 01, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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		=100/0	polymorphism

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;