ADAMTS10

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 10, the group of ADAM metallopeptidases with thrombospondin type 1 motif

Gene summary

This gene belongs to the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin type-1 motifs) family of zinc-dependent proteases. ADAMTS proteases are complex secreted enzymes containing a prometalloprotease domain of the reprolysin type attached to an ancillary domain with a highly conserved structure that includes at least one thrombospondin type 1 repeat. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. The product of this gene plays a major role in growth and in skin, lens, and heart development. It is also a candidate gene for autosomal recessive Weill-Marchesani syndrome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_030957.4

Inheritance

AR, AD

ClinVar variants

P:40U:367B:354

Top phenotype

Weill-Marchesani syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr19:8,580,240-8,610,735

External References & Databases

Ensembl (ENSG00000142303)

Transcript & Mutation Effects

hg38 • Region Span ~30.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Weill-Marchesani syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010194

Submitter: Labcorp Genetics (formerly Invitae)

Weill-Marchesani syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010194

Submitter: PanelApp Australia

Weill-Marchesani syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018096

Submitter: Orphanet

Weill-Marchesani syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010194

Submitter: G2P

Weill-Marchesani syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010194

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Weill-Marchesani syndrome 1AR

Manifestation: Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular; Ophthalmologic

Rationale: Individuals can have cardiac anomalies, including long QTc, and awareness may allow for preventive/medical management, which may decrease morbidity and mortality; As the condition can include glaucoma, surveillance can allow early interventions that may potentially be beneficial related to preservation of visual status

Refs: 11941487; 14598350; 15368195; 17663475

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS10 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 908

Inborn genetic diseasesTotal: 143

not specifiedTotal: 105

Weill-Marchesani syndromeTotal: 81

Weill-Marchesani syndrome 1Total: 50

ADAMTS10-related disorderTotal: 35

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030957.4. 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			5 clinvar	329 clinvar	3 clinvar	337
missense	2 clinvar	8 clinvar	356 clinvar	20 clinvar	2 clinvar	388
nonsense	11 clinvar	2 clinvar	2 clinvar			15
start loss						0
frameshift	8 clinvar	1 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	3 clinvar			11
Total	22	18	367	349	5	761

Highest pathogenic variant AF is 0.0000065799863

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030957.4	RefSeq	NP_112219.3	24	MANE Select
ENST00000597188.6	Ensembl	ENSP00000471851.1	24	MANE Select
NM_001282352.2	RefSeq	NP_001269281.1	13	Standard
ENST00000270328.8	Ensembl	ENSP00000270328.4	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
O-glycosylation of TSR domain-containing proteins
O-linked glycosylation

Biological Process

proteolysis
biological_process

Molecular Function

molecular_function
metalloendopeptidase activity
protein binding
metal ion binding

Cellular Component

microfibril
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000270328
Coding exons: 24
Length: 30495
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.63	446	720	0.620	0.0000507	7077
Missense (PolyPhen)		109	255.08	0.42732		2605
Synonymous	0.782	294	312	0.944	0.0000238	2241
Loss of Function	5.67	12	59.0	0.204	0.00000313	618

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Metalloprotease that participate in microfibrils assembly. Microfibrils are extracellular matrix components occurring independently or along with elastin in the formation of elastic tissues. {ECO:0000269|PubMed:21402694}.;
Disease: DISEASE: Weill-Marchesani syndrome 1 (WMS1) [MIM:277600]: A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma. {ECO:0000269|PubMed:15368195, ECO:0000269|PubMed:18567016}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.476
RVIS EVS: -1.32
RVIS percentile EVS: 4.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.221

Gene Damage Prediction

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