NM_004969.4:c.99-1193C>T

Variant names:

• chr10-92538743-G-A
• rs17107721
• NM_004969.4:c.99-1193C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004969.4(IDE):​c.99-1193C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 148,152 control chromosomes in the GnomAD database, including 167 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 0.044 (167 hom., cov: 31)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.484
• 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=-0.88).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0435 (6447/148152) while in subpopulation AFR AF = 0.0475 (1914/40282). AF 95% confidence interval is 0.0457. There are 167 homozygotes in GnomAd4. There are 2994 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 167 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004969.4. 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
	IDE	NM_004969.4	MANE Select	c.99-1193C>T		intron	N/A	NP_004960.2
	IDE	NM_001322793.2		c.99-1193C>T		intron	N/A	NP_001309722.1
	IDE	NM_001322794.2		c.99-1193C>T		intron	N/A	NP_001309723.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.99-1193C>T		intron	N/A	ENSP00000265986.6
	IDE	ENST00000478361.6	TSL:1	n.*309-1193C>T		intron	N/A	ENSP00000473506.1
	IDE	ENST00000971392.1		c.99-1193C>T		intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6442 AN: 148048 Hom.: 168 Cov.: 31

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00996

Gnomad AMR AF: 0.0445

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.00121

Gnomad SAS AF: 0.0309

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0575

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

GnomAD4 genome AF: 0.0435 AC: 6447 AN: 148152 Hom.: 167 Cov.: 31 AF XY: 0.0416 AC XY: 2994 AN XY: 71910

African (AFR) AF: 0.0475 AC: 1914 AN: 40282

American (AMR) AF: 0.0444 AC: 653 AN: 14710

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 611 AN: 3456

East Asian (EAS) AF: 0.00121 AC: 6 AN: 4958

South Asian (SAS) AF: 0.0306 AC: 141 AN: 4614

European-Finnish (FIN) AF: 0.00895 AC: 85 AN: 9494

Middle Eastern (MID) AF: 0.0793 AC: 23 AN: 290

European-Non Finnish (NFE) AF: 0.0429 AC: 2888 AN: 67388

Other (OTH) AF: 0.0569 AC: 117 AN: 2056

Alfa AF: 0.0123 Hom.: 5

Bravo AF: 0.0468

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

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: rs17107721; hg19: chr10-94298500;