ADAMTS8

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 8, the group of ADAM metallopeptidases with thrombospondin type 1 motif

Gene summary

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme contains two C-terminal TS motifs, and disrupts angiogenesis in vivo. A number of disorders have been mapped in the vicinity of this gene, most notably lung neoplasms. Reduced expression of this gene has been observed in multiple human cancers and this gene has been proposed as a potential tumor suppressor. [provided by RefSeq, Feb 2016]

MANE transcript

NM_007037.6

Inheritance

—

ClinVar variants

U:160B:6

Top phenotype

Oromandibular-limb hypogenesis spectrum

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr11:130,404,923-130,428,609

External References & Databases

Ensembl (ENSG00000134917)

Transcript & Mutation Effects

hg38 • Region Span ~23.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS8 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 161

not providedTotal: 2

Oromandibular-limb hypogenesis spectrumTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007037.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				1 clinvar		1
missense			159 clinvar	5 clinvar		164
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	160	6	0	166

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007037.6	RefSeq	NP_008968.4	9	MANE Select
ENST00000257359.7	Ensembl	ENSP00000257359.6	9	MANE Select
ENST00000875535.1	Ensembl	ENSP00000545594.1	9	Standard
ENST00000875535.2	Ensembl	ENSP00000545594.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Extracellular matrix organization
Degradation of the extracellular matrix
O-glycosylation of TSR domain-containing proteins

Biological Process

proteolysis
negative regulation of cell population proliferation
phosphate ion transmembrane transport

Molecular Function

metalloendopeptidase activity
integrin binding
heparin binding
metallopeptidase activity
zinc ion binding

Cellular Component

collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000257359
Coding exons: 9
Length: 24069
Individuals with no LoFs: 124735
Homozygous LoFs: 1
Heterozygous LoFs: 116
Defined: 124852
p: 0.000469

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.518	469	502	0.935	0.0000301	5641
Missense (PolyPhen)		203	210.29	0.96532		2316
Synonymous	-0.309	230	224	1.03	0.0000145	1857
Loss of Function	1.97	21	33.3	0.631	0.00000169	357

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00027	0.00026	rare
Latino/Admixed American	0.00067	0.00067	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00045	0.00045	rare
Finnish	0.00084	0.00084	rare
European (Non-Finnish)	0.00044	0.00042	rare
South Asian	0.00033	0.00033	rare
Other	0.00099	0.00099	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has anti-angiogenic properties.;

Recessive Scores

pRec: 0.123

Intolerance Scores

LoFtool: 0.513
RVIS EVS: 0.67
RVIS percentile EVS: 84.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.394

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High