19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr19-7184640-G-GGAGAGAGAGAGAGAGAGAGA
• rs3835070
• NM_000208.4:c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000208.4(INSR):​c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 0)
  • Exomes 𝑓: 0.00019 (5 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Benign/Likely 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 -12 ACMG points.

• BP6: Variant 19-7184640-G-GGAGAGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGAGAGAGAGAGAGAGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 728898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 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.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-23_653-4dupTCTCTCTCTCTCTCTCTCTC		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_653-3insTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 664 AN: 141858 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.000881

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000166

Gnomad OTH AF: 0.00467

GnomAD4 exome AF: 0.000192 AC: 237 AN: 1233760 Hom.: 5 Cov.: 17 AF XY: 0.000154 AC XY: 95 AN XY: 617868

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00551 AC: 136 AN: 24704

American (AMR) AF: 0.000632 AC: 25 AN: 39546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23124

East Asian (EAS) AF: 0.00 AC: 0 AN: 36490

South Asian (SAS) AF: 0.0000426 AC: 3 AN: 70478

European-Finnish (FIN) AF: 0.000127 AC: 6 AN: 47250

Middle Eastern (MID) AF: 0.00128 AC: 5 AN: 3918

European-Non Finnish (NFE) AF: 0.0000235 AC: 22 AN: 937120

Other (OTH) AF: 0.000782 AC: 40 AN: 51130

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00467 AC: 663 AN: 141952 Hom.: 8 Cov.: 0 AF XY: 0.00473 AC XY: 326 AN XY: 68860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0168 AC: 603 AN: 35984

American (AMR) AF: 0.00245 AC: 35 AN: 14280

Ashkenazi Jewish (ASJ) AF: 0.000881 AC: 3 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4986

South Asian (SAS) AF: 0.00 AC: 0 AN: 4496

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9412

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.000166 AC: 11 AN: 66288

Other (OTH) AF: 0.00463 AC: 9 AN: 1942

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

May 14, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Benign:1

Dec 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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;