Genetic Variant IDE:p.Gly1001Asp (chr10-92454502-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004969.4(IDE):c.3002G>A(p.Gly1001Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1001V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IDE
NM_004969.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.25

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3504042).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
IDE	NM_004969.4	MANE Select	c.3002G>A	p.Gly1001Asp	missense	Exon 25 of 25	NP_004960.2	P14735-1
IDE	NM_001322793.2		c.3002G>A	p.Gly1001Asp	missense	Exon 25 of 25	NP_001309722.1	A0A3B3ISG5
IDE	NM_001322794.2		c.2885G>A	p.Gly962Asp	missense	Exon 25 of 25	NP_001309723.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDE	ENST00000265986.11	TSL:1 MANE Select	c.3002G>A	p.Gly1001Asp	missense	Exon 25 of 25	ENSP00000265986.6	P14735-1
IDE	ENST00000971392.1		c.3143G>A	p.Gly1048Asp	missense	Exon 26 of 26	ENSP00000641451.1
IDE	ENST00000857320.1		c.3107G>A	p.Gly1036Asp	missense	Exon 26 of 26	ENSP00000527379.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111830

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-0.057

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0093

MetaRNN

Benign

0.35

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.41

PhyloP100

7.3

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.30

REVEL

Benign

0.19

Sift

Benign

0.24

Sift4G

Benign

0.18

Polyphen

0.0030

Vest4

0.32

MutPred

0.44

Gain of relative solvent accessibility (P = 0.0479)

MVP

0.25

MPC

0.40

ClinPred

0.89

GERP RS

5.9

Varity_R

0.24

gMVP

0.34

Mutation Taster

=54/46

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over