10-92475975-T-C

Position:

• chr10-92475975-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004969.4(IDE):​c.1904A>G​(p.Asn635Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000742 in 1,347,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: IDE NM_004969.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17859077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDE	NM_004969.4	c.1904A>G	p.Asn635Ser	missense_variant	16/25	ENST00000265986.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDE	ENST00000265986.11	c.1904A>G	p.Asn635Ser	missense_variant	16/25	1	NM_004969.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.42e-7 AC: 1 AN: 1347934 Hom.: 0 Cov.: 20 AF XY: 0.00000149 AC XY: 1 AN XY: 672624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.79e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.1904A>G (p.N635S) alteration is located in exon 16 (coding exon 16) of the IDE gene. This alteration results from a A to G substitution at nucleotide position 1904, causing the asparagine (N) at amino acid position 635 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.19	.;.;T
Eigen	Benign	-0.036
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.74	.;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.56	T;.;T
Sift4G	Benign	0.19	T;.;T
Polyphen		0.025	.;.;B
Vest4		0.18
MutPred		0.46		.;Gain of disorder (P = 0.0693);Gain of disorder (P = 0.0693);
MVP		0.54
MPC		0.25
ClinPred		0.70	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs1409530515; hg19: chr10-94235732;