chr19-7184640-G-GGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr19-7184640-G-GGAGAGAGAGAGAGAGAGAGAGAGA
• rs3835070
• NM_000208.4:c.653-4_653-3insTCTCTCTCTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000208.4(INSR):​c.653-4_653-3insTCTCTCTCTCTCTCTCTCTCTCTC 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.653-4_653-3insTCTCTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-4_653-3insTCTCTCTCTCTCTCTCTCTCTCTC		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_653-3insTCTCTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTCTCTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTCTCTCTCTCTCTCTCTCTCTCTC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000633 AC: 9 AN: 142282 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000243 AC: 3 AN: 1233952 Hom.: 0 Cov.: 17 AF XY: 0.00000324 AC XY: 2 AN XY: 617968

African (AFR) AF: 0.0000403 AC: 1 AN: 24826

American (AMR) AF: 0.00 AC: 0 AN: 39560

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 70478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47250

Middle Eastern (MID) AF: 0.000255 AC: 1 AN: 3920

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 937142

Other (OTH) AF: 0.00 AC: 0 AN: 51162

GnomAD4 genome AF: 0.0000632 AC: 9 AN: 142372 Hom.: 0 Cov.: 0 AF XY: 0.0000435 AC XY: 3 AN XY: 69044

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

African (AFR) AF: 0.000247 AC: 9 AN: 36384

American (AMR) AF: 0.00 AC: 0 AN: 14296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 9414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66288

Other (OTH) AF: 0.00 AC: 0 AN: 1944

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000128496), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0

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;