NM_004969.4:c.785-1257A>G

Variant names:

• chr10-92511419-T-C
• rs17445028
• NM_004969.4:c.785-1257A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004969.4(IDE):​c.785-1257A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,036 control chromosomes in the GnomAD database, including 2,895 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 0.19 (2895 hom., cov: 30)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDE	NM_004969.4	c.785-1257A>G		intron_variant	Intron 5 of 24	ENST00000265986.11	NP_004960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11	c.785-1257A>G		intron_variant	Intron 5 of 24	1	NM_004969.4	ENSP00000265986.6

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28211 AN: 151918 Hom.: 2894 Cov.: 30

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.186 AC: 28216 AN: 152036 Hom.: 2895 Cov.: 30 AF XY: 0.188 AC XY: 13954 AN XY: 74318

African (AFR) AF: 0.158 AC: 6568 AN: 41464

American (AMR) AF: 0.162 AC: 2478 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3472

East Asian (EAS) AF: 0.0457 AC: 237 AN: 5188

South Asian (SAS) AF: 0.118 AC: 568 AN: 4820

European-Finnish (FIN) AF: 0.281 AC: 2961 AN: 10538

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14107 AN: 67964

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.193 Hom.: 484

Bravo AF: 0.174

Asia WGS AF: 0.121 AC: 421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17445028; hg19: chr10-94271176;