NM_004969.4:c.99-10946A>G

Variant names:

• chr10-92548496-T-C
• rs11187064
• NM_004969.4:c.99-10946A>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.99-10946A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 151,376 control chromosomes in the GnomAD database, including 3,475 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 (3475 hom., cov: 31)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 10 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 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.99-10946A>G		intron	N/A	NP_004960.2	P14735-1
	IDE	NM_001322793.2		c.99-10946A>G		intron	N/A	NP_001309722.1	A0A3B3ISG5
	IDE	NM_001322794.2		c.99-10946A>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.99-10946A>G		intron	N/A	ENSP00000265986.6	P14735-1
	IDE	ENST00000478361.6	TSL:1	n.*308+6226A>G		intron	N/A	ENSP00000473506.1	R4GN65
	IDE	ENST00000971392.1		c.99-10946A>G		intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 29919 AN: 151260 Hom.: 3476 Cov.: 31

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.198 AC: 29912 AN: 151376 Hom.: 3475 Cov.: 31 AF XY: 0.199 AC XY: 14730 AN XY: 73926

African (AFR) AF: 0.0967 AC: 3986 AN: 41232

American (AMR) AF: 0.175 AC: 2651 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 891 AN: 3464

East Asian (EAS) AF: 0.0462 AC: 235 AN: 5090

South Asian (SAS) AF: 0.130 AC: 622 AN: 4782

European-Finnish (FIN) AF: 0.321 AC: 3342 AN: 10424

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17552 AN: 67894

Other (OTH) AF: 0.194 AC: 408 AN: 2104

Alfa AF: 0.243 Hom.: 9068

Bravo AF: 0.182

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.88
PhyloP100		0.061
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: rs11187064; hg19: chr10-94308253;