rs1999764

Variant names:

• chr10-92560382-T-C
• rs1999764
• NM_004969.4:c.98+13540A>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.98+13540A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,226 control chromosomes in the GnomAD database, including 924 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 0.10 (924 hom., cov: 31)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221
• Publications: 4 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=-0.69).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.161 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.98+13540A>G		intron	N/A	NP_004960.2	P14735-1
	IDE	NM_001322793.2		c.98+13540A>G		intron	N/A	NP_001309722.1	A0A3B3ISG5
	IDE	NM_001322794.2		c.98+13540A>G		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.98+13540A>G		intron	N/A	ENSP00000265986.6	P14735-1
	IDE	ENST00000478361.6	TSL:1	n.99-1167A>G		intron	N/A	ENSP00000473506.1	R4GN65
	IDE	ENST00000971392.1		c.98+13540A>G		intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15504 AN: 152108 Hom.: 919 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0541

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0877

Gnomad OTH AF: 0.0918

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

GnomAD4 genome AF: 0.102 AC: 15544 AN: 152226 Hom.: 924 Cov.: 31 AF XY: 0.103 AC XY: 7684 AN XY: 74424

African (AFR) AF: 0.115 AC: 4786 AN: 41552

American (AMR) AF: 0.153 AC: 2331 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3466

East Asian (EAS) AF: 0.127 AC: 656 AN: 5176

South Asian (SAS) AF: 0.170 AC: 823 AN: 4828

European-Finnish (FIN) AF: 0.0541 AC: 574 AN: 10618

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0877 AC: 5966 AN: 68012

Other (OTH) AF: 0.0937 AC: 198 AN: 2114

Alfa AF: 0.0986 Hom.: 102

Bravo AF: 0.109

Asia WGS AF: 0.135 AC: 469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.8
DANN	Benign	0.92
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1999764; hg19: chr10-94320139;