NM_004969.4:c.99-17497T>C

Variant names:

• chr10-92555047-A-G
• rs7908111
• NM_004969.4:c.99-17497T>C

Variant summary

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

The NM_004969.4(IDE):​c.99-17497T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 152,152 control chromosomes in the GnomAD database, including 55,043 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 0.85 (55043 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.924
• Publications: 7 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	NM_004969.4	MANE Select	c.99-17497T>C		intron	N/A	NP_004960.2	P14735-1
	IDE	NM_001322793.2		c.99-17497T>C		intron	N/A	NP_001309722.1	A0A3B3ISG5
	IDE	NM_001322794.2		c.99-17497T>C		intron	N/A	NP_001309723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.99-17497T>C		intron	N/A	ENSP00000265986.6	P14735-1
	IDE	ENST00000478361.6	TSL:1	n.*224-130T>C		intron	N/A	ENSP00000473506.1	R4GN65
	IDE	ENST00000971392.1		c.99-17497T>C		intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128986 AN: 152034 Hom.: 54995 Cov.: 31

Gnomad AFR AF: 0.931

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.824

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

GnomAD4 genome AF: 0.848 AC: 129091 AN: 152152 Hom.: 55043 Cov.: 31 AF XY: 0.849 AC XY: 63160 AN XY: 74384

African (AFR) AF: 0.931 AC: 38655 AN: 41512

American (AMR) AF: 0.807 AC: 12317 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 2997 AN: 3472

East Asian (EAS) AF: 0.919 AC: 4765 AN: 5184

South Asian (SAS) AF: 0.840 AC: 4053 AN: 4826

European-Finnish (FIN) AF: 0.860 AC: 9105 AN: 10584

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.801 AC: 54460 AN: 67990

Other (OTH) AF: 0.823 AC: 1736 AN: 2110

Alfa AF: 0.816 Hom.: 24813

Bravo AF: 0.848

Asia WGS AF: 0.874 AC: 3037 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	4.6
DANN	Benign	0.32
PhyloP100		-0.92
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: rs7908111; hg19: chr10-94314804;