NM_004969.4:c.2866G>T

Variant names:

• chr10-92456389-C-A
• rs375559999
• NM_004969.4:c.2866G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004969.4(IDE):​c.2866G>T​(p.Val956Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V956I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDE NM_004969.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744

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.2866G>T	p.Val956Phe	missense	Exon 23 of 25	NP_004960.2	P14735-1
	IDE	NM_001322793.2		c.2866G>T	p.Val956Phe	missense	Exon 23 of 25	NP_001309722.1	A0A3B3ISG5
	IDE	NM_001322794.2		c.2749G>T	p.Val917Phe	missense	Exon 23 of 25	NP_001309723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.2866G>T	p.Val956Phe	missense	Exon 23 of 25	ENSP00000265986.6	P14735-1
	IDE	ENST00000971392.1		c.3007G>T	p.Val1003Phe	missense	Exon 24 of 26	ENSP00000641451.1
	IDE	ENST00000857320.1		c.2971G>T	p.Val991Phe	missense	Exon 24 of 26	ENSP00000527379.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.49		Gain of catalytic residue at V956 (P = 0.1353)
MVP		0.64
MPC		1.2
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.89
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs375559999; hg19: chr10-94216146;