ADAMTS4

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 4, 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 this 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 enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MANE transcript

NM_005099.6

Inheritance

—

ClinVar variants

U:133B:9

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr1:161,184,302-161,199,054

External References & Databases

Ensembl (ENSG00000158859)

Transcript & Mutation Effects

hg38 • Region Span ~14.8 kb

Loading mutation effect viewer...

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 ADAMTS4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 131

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005099.6. 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				3 clinvar		3
missense			129 clinvar	6 clinvar		135
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	133	9	0	142

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005099.6	RefSeq	NP_005090.3	9	MANE Select
ENST00000367996.6	Ensembl	ENSP00000356975.4	9	MANE Select
NM_001320336.3	RefSeq	NP_001307265.1	9	Standard
ENST00000367995.3	Ensembl	ENSP00000356974.3	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endochondral Ossification
Post-translational protein modification
Metabolism of proteins
Extracellular matrix organization
Degradation of the extracellular matrix

Biological Process

skeletal system development
proteolysis
extracellular matrix disassembly

Molecular Function

protease binding
metalloendopeptidase activity
protein binding
peptidase activity
metallopeptidase activity

Cellular Component

extracellular region
extracellular space
nuclear speck
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367996
Coding exons: 9
Length: 14749
Individuals with no LoFs: 125679
Homozygous LoFs: 0
Heterozygous LoFs: 69
Defined: 125748
p: 0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	454	529	0.859	0.0000328	5321
Missense (PolyPhen)		170	219.24	0.77542		2269
Synonymous	0.587	209	220	0.950	0.0000133	1829
Loss of Function	2.85	15	32.5	0.461	0.00000173	337

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00066	0.00065	rare
Finnish	0.00063	0.00060	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00029	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site.;

Recessive Scores

pRec: 0.193

Intolerance Scores

LoFtool: 0.447
RVIS EVS: 0.09
RVIS percentile EVS: 60.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.172

Gene Damage Prediction

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