NM_004969.4:c.1740-193_1740-190delACAC

Variant names:

• chr10-92479610-AGTGT-A
• rs3831274
• NM_004969.4:c.1740-193_1740-190delACAC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004969.4(IDE):​c.1740-193_1740-190delACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 462,888 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0062 (1 hom.)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.478
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.0144) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 1).

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.1740-193_1740-190delACAC		intron	N/A	NP_004960.2
	IDE	NM_001322793.2		c.1740-825_1740-822delACAC		intron	N/A	NP_001309722.1
	IDE	NM_001322794.2		c.1623-193_1623-190delACAC		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.1740-193_1740-190delACAC		intron	N/A	ENSP00000265986.6
	IDE	ENST00000478361.6	TSL:1	n.*2074-193_*2074-190delACAC		intron	N/A	ENSP00000473506.1
	IDE	ENST00000679069.1		n.3119_3122delACAC		non_coding_transcript_exon	Exon 15 of 25

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 72 AN: 150150 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000534

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.00617 AC: 1930 AN: 312738 Hom.: 1 AF XY: 0.00621 AC XY: 1016 AN XY: 163544

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00151 AC: 15 AN: 9926

American (AMR) AF: 0.00424 AC: 60 AN: 14148

Ashkenazi Jewish (ASJ) AF: 0.00521 AC: 52 AN: 9986

East Asian (EAS) AF: 0.0158 AC: 334 AN: 21158

South Asian (SAS) AF: 0.00907 AC: 236 AN: 26008

European-Finnish (FIN) AF: 0.00639 AC: 136 AN: 21270

Middle Eastern (MID) AF: 0.00434 AC: 6 AN: 1382

European-Non Finnish (NFE) AF: 0.00519 AC: 988 AN: 190226

Other (OTH) AF: 0.00553 AC: 103 AN: 18634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000480 AC: 72 AN: 150150 Hom.: 0 Cov.: 0 AF XY: 0.000382 AC XY: 28 AN XY: 73222

African (AFR) AF: 0.000586 AC: 24 AN: 40962

American (AMR) AF: 0.000332 AC: 5 AN: 15042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.000629 AC: 3 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000534 AC: 36 AN: 67388

Other (OTH) AF: 0.00146 AC: 3 AN: 2058

Alfa AF: 0.00 Hom.: 211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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: rs3831274; hg19: chr10-94239367;