19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGA

Position:

• chr19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.653-5_653-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,315,650 control chromosomes in the GnomAD database, including 7,668 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1551 hom., cov: 0)
  • Exomes 𝑓: 0.13 (6117 hom.)
• Consequence: INSR NM_000208.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.176

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 -16 ACMG points.

• BP6: Variant 19-7184640-GGA-G is Benign according to our data. Variant chr19-7184640-GGA-G is described in ClinVar as [Benign]. Clinvar id is 196236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7184640-GGA-G is described in Lovd as [Benign]. Variant chr19-7184640-GGA-G is described in Lovd as [Likely_benign]. Variant chr19-7184640-GGA-G is described in Lovd as [Benign]. Variant chr19-7184640-GGA-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.653-5_653-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.653-5_653-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
INSR	XM_011527988.3	c.653-5_653-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
INSR	XM_011527989.4	c.653-5_653-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.653-5_653-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.653-5_653-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P3
INSR	ENST00000598216.1	n.628-5_628-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 19520 AN: 142016 Hom.: 1550 Cov.: 0

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.144

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.238 AC: 32849 AN: 137742 Hom.: 1340 AF XY: 0.243 AC XY: 18641 AN XY: 76688

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.129 AC: 151247 AN: 1173544 Hom.: 6117 AF XY: 0.133 AC XY: 77709 AN XY: 584838

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.137 AC: 19523 AN: 142106 Hom.: 1551 Cov.: 0 AF XY: 0.141 AC XY: 9736 AN XY: 68910

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3835070; hg19: chr19-7184651;