rs1555735951

Positions:

• chr19-7126584-CATCACTGGCA-CCTTCC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP2

The NM_000208.4(INSR):​c.3003_3012delTGCCAGTGATinsGGAAG​(p.Ser1001fs) variant causes a frameshift, missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INSR NM_000208.4 frameshift, missense, splice_region
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.57

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), INSR. . Gene score misZ 3.8314 (greater than the threshold 3.09). Trascript score misZ 5.4593 (greater than threshold 3.09). GenCC has associacion of gene with insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.3003_3012delTGCCAGTGATinsGGAAG	p.Ser1001fs	frameshift_variant, missense_variant, splice_region_variant	16/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2967_2976delTGCCAGTGATinsGGAAG	p.Ser989fs	frameshift_variant, missense_variant, splice_region_variant	15/21		NP_001073285.1
INSR	XM_011527988.3	c.3000_3009delTGCCAGTGATinsGGAAG	p.Ser1000fs	frameshift_variant, missense_variant, splice_region_variant	16/22		XP_011526290.2
INSR	XM_011527989.4	c.2964_2973delTGCCAGTGATinsGGAAG	p.Ser988fs	frameshift_variant, missense_variant, splice_region_variant	15/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.3003_3012delTGCCAGTGATinsGGAAG	p.Ser1001fs	frameshift_variant, missense_variant, splice_region_variant	16/22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2967_2976delTGCCAGTGATinsGGAAG	p.Ser989fs	frameshift_variant, missense_variant, splice_region_variant	15/21	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Leprechaunism syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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: rs1555735951; hg19: chr19-7126596;