19-7184640-G-GGA

Variant names:

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

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_653-4dupTC 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

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-GGA is Benign according to our data. Variant chr19-7184640-G-GGA is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-5_653-4dupTC		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-5_653-4dupTC		splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-5_653-4dupTC		splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-5_653-4dupTC		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_653-3insTC		splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-4_653-3insTC		splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-4_628-3insTC		splice_region_variant, intron_variant	Intron 2 of 9	1

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

GnomAD3 exomes AF: 0.0869 AC: 11968 AN: 137742 Hom.: 157 AF XY: 0.0904 AC XY: 6935 AN XY: 76688

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 SAS exome AF: 0.154

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

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.0428

Gnomad4 EAS exome AF: 0.0659

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.0638

Gnomad4 NFE exome AF: 0.0495

Gnomad4 OTH exome AF: 0.0766

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

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0552

Gnomad4 EAS AF: 0.0799

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.0725

Gnomad4 NFE AF: 0.0916

Gnomad4 OTH AF: 0.151

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

not specified Benign:3

Oct 23, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Genetic Services Laboratory, University of Chicago

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 v4.3

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;