Genetic Variant NM_004969.4:c.491+44T>C (chr10-92534534-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004969.4(IDE):c.491+44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,014,588 control chromosomes in the GnomAD database, including 28,699 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 ( 3473 hom., cov: 32)

Exomes 𝑓: 0.23 ( 25226 hom. )

Consequence

IDE
NM_004969.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.102

Publications

17 publications found

Variant links:

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]

IDE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDE	NM_004969.4	MANE Select	c.491+44T>C	intron	N/A	NP_004960.2	P14735-1
IDE	NM_001322793.2		c.491+44T>C	intron	N/A	NP_001309722.1	A0A3B3ISG5
IDE	NM_001322794.2		c.491+44T>C	intron	N/A	NP_001309723.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDE	ENST00000265986.11	TSL:1 MANE Select	c.491+44T>C	intron	N/A	ENSP00000265986.6	P14735-1
IDE	ENST00000478361.6	TSL:1	n.*701+44T>C	intron	N/A	ENSP00000473506.1	R4GN65
IDE	ENST00000971392.1		c.491+44T>C	intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29939

AN:

151986

Hom.:

3474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0963

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.0458

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.206

AC:

45199

AN:

219692

AF XY:

0.208

show subpopulations

Gnomad AFR exome

AF:

0.0924

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.0450

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.223

GnomAD4 exome

AF:

0.229

AC:

197857

AN:

862484

Hom.:

25226

Cov.:

AF XY:

0.227

AC XY:

101691

AN XY:

448344

show subpopulations

African (AFR)

AF:

0.0911

AC:

1891

AN:

20752

American (AMR)

AF:

0.131

AC:

4455

AN:

34094

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

5349

AN:

20542

East Asian (EAS)

AF:

0.0341

AC:

1249

AN:

36656

South Asian (SAS)

AF:

0.139

AC:

9215

AN:

66458

European-Finnish (FIN)

AF:

0.301

AC:

15480

AN:

51368

Middle Eastern (MID)

AF:

0.220

AC:

972

AN:

4426

European-Non Finnish (NFE)

AF:

0.256

AC:

150511

AN:

588240

Other (OTH)

AF:

0.219

AC:

8735

AN:

39948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

7546

15092

22637

30183

37729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3404

6808

10212

13616

17020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.197

AC:

29932

AN:

152104

Hom.:

3473

Cov.:

AF XY:

0.198

AC XY:

14741

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0962

AC:

3992

AN:

41504

American (AMR)

AF:

0.174

AC:

2654

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

895

AN:

3472

East Asian (EAS)

AF:

0.0455

AC:

236

AN:

5182

South Asian (SAS)

AF:

0.129

AC:

621

AN:

4826

European-Finnish (FIN)

AF:

0.318

AC:

3352

AN:

10550

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17549

AN:

67972

Other (OTH)

AF:

0.194

AC:

409

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1179

2358

3536

4715

5894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.230

Hom.:

12053

Bravo

AF:

0.181

Asia WGS

AF:

0.116

AC:

403

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.68

(source)

DANN

Benign

0.61

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over