19-7184640-G-GGAGAGA

Variant names:

• chr19-7184640-G-GGAGAGA
• rs3835070
• NM_000208.4:c.653-9_653-4dupTCTCTC

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000208.4(INSR):​c.653-9_653-4dupTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.04

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 -12 ACMG points.

• BP6: Variant 19-7184640-G-GGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 1336488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000128 (158/1233896) while in subpopulation AFR AF= 0.00121 (30/24812). AF 95% confidence interval is 0.00087. There are 1 homozygotes in gnomad4_exome. There are 89 alleles in male gnomad4_exome subpopulation. Median coverage is 17. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-9_653-4dupTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-9_653-4dupTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-9_653-4dupTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-9_653-4dupTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.653-4_653-3insTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-4_653-3insTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-4_628-3insTCTCTC		splice_region_variant, intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.000162 AC: 23 AN: 142298 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00353

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000106

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000479 AC: 66 AN: 137742 Hom.: 2 AF XY: 0.000443 AC XY: 34 AN XY: 76688

Gnomad AFR exome AF: 0.00342

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00163

Gnomad EAS exome AF: 0.00140

Gnomad SAS exome AF: 0.000319

Gnomad FIN exome AF: 0.000161

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.000289

GnomAD4 exome AF: 0.000128 AC: 158 AN: 1233896 Hom.: 1 Cov.: 17 AF XY: 0.000144 AC XY: 89 AN XY: 617932

Gnomad4 AFR exome AF: 0.00121

Gnomad4 AMR exome AF: 0.000152

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.000466

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.0000635

Gnomad4 NFE exome AF: 0.0000395

Gnomad4 OTH exome AF: 0.000293

GnomAD4 genome AF: 0.000162 AC: 23 AN: 142388 Hom.: 0 Cov.: 0 AF XY: 0.0000724 AC XY: 5 AN XY: 69050

Gnomad4 AFR AF: 0.000110

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00353

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000106

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 18, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

INSR-related disorder Benign:1

Dec 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3835070; hg19: chr19-7184651;