19-7184640-G-GGAGAGAGA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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-G-GGAGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGAGA is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-11_653-4dupTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-11_653-4dupTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-11_653-4dupTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-11_653-4dupTCTCTCTC		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_653-3insTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-4_653-3insTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-4_628-3insTCTCTCTC		splice_region_variant, intron_variant	Intron 2 of 9	1

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

GnomAD3 exomes AF: 0.00118 AC: 163 AN: 137742 Hom.: 1 AF XY: 0.00106 AC XY: 81 AN XY: 76688

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 SAS exome AF: 0.000265

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

Gnomad4 AFR exome AF: 0.00768

Gnomad4 AMR exome AF: 0.000657

Gnomad4 ASJ exome AF: 0.00112

Gnomad4 EAS exome AF: 0.00722

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.0000212

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00108

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

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.00182

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.000222

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000181

Gnomad4 OTH AF: 0.00309

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 v4.3

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;