rs4646955

Positions:

• chr10-92534534-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004969.4(IDE):​c.491+44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,014,588 control chromosomes in the GnomAD database, including 28,699 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3473 hom., cov: 32)
  • Exomes 𝑓: 0.23 (25226 hom.)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102

Genes affected

IDE (HGNC:5381): (insulin degrading enzyme) This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDE	NM_004969.4	c.491+44T>C		intron_variant		ENST00000265986.11	NP_004960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11	c.491+44T>C		intron_variant		1	NM_004969.4	ENSP00000265986	P1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29939 AN: 151986 Hom.: 3474 Cov.: 32

Gnomad AFR AF: 0.0963

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.195

GnomAD3 exomes AF: 0.206 AC: 45199 AN: 219692 Hom.: 5387 AF XY: 0.208 AC XY: 24844 AN XY: 119568

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.0450

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.229 AC: 197857 AN: 862484 Hom.: 25226 Cov.: 11 AF XY: 0.227 AC XY: 101691 AN XY: 448344

Gnomad4 AFR exome AF: 0.0911

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.0341

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.219

GnomAD4 genome AF: 0.197 AC: 29932 AN: 152104 Hom.: 3473 Cov.: 32 AF XY: 0.198 AC XY: 14741 AN XY: 74346

Gnomad4 AFR AF: 0.0962

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.0455

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.194

Alfa AF: 0.241 Hom.: 7971

Bravo AF: 0.181

Asia WGS AF: 0.116 AC: 403 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4646955; hg19: chr10-94294291;