ADAMTS1

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 1, 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 motif) 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 protein encoded by this gene contains two disintegrin loops and three C-terminal TS motifs and has anti-angiogenic activity. The expression of this gene may be associated with various inflammatory processes as well as development of cancer cachexia. This gene is likely to be necessary for normal growth, fertility, and organ morphology and function. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006988.5

Inheritance

AR, AD

ClinVar variants

P:1U:130B:23

Top phenotype

Premature ovarian failure

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr21:26,835,755-26,845,409

External References & Databases

Ensembl (ENSG00000154734)

Transcript & Mutation Effects

hg38 • Region Span ~9.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

autosomal dominant prognathismLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008312

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 130

not providedTotal: 23

Premature ovarian failureTotal: 1

Nonsyndromic hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006988.5. 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	4 clinvar	6 clinvar	11
missense		1 clinvar	127 clinvar	10 clinvar	3 clinvar	141
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	1	130	14	9	154

Highest pathogenic variant AF is 0.000013010379

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006988.5	RefSeq	NP_008919.3	9	MANE Select
ENST00000284984.8	Ensembl	ENSP00000284984.2	9	MANE Select
ENST00000451462.6	Ensembl	ENSP00000403404.2	8	Standard
ENST00000451462.7	Ensembl	ENSP00000403404.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

VEGFA-VEGFR2 Signaling Pathway
Endochondral Ossification
Post-translational protein modification
Metabolism of proteins
Extracellular matrix organization

Biological Process

ovulation from ovarian follicle
kidney development
proteolysis
integrin-mediated signaling pathway
negative regulation of cell population proliferation

Molecular Function

metalloendopeptidase activity
heparin binding
metallopeptidase activity
zinc ion binding

Cellular Component

basement membrane
cytoplasmic vesicle
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000284984
Coding exons: 9
Length: 9663
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.667	504	548	0.920	0.0000283	6267
Missense (PolyPhen)		212	257.71	0.82264		3002
Synonymous	-0.0517	232	231	1.00	0.0000133	1895
Loss of Function	4.63	8	39.3	0.204	0.00000201	453

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00027	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves aggrecan, a cartilage proteoglycan, at the '1938-Glu-|-Leu-1939' site (within the chondroitin sulfate attachment domain), and may be involved in its turnover (By similarity). Has angiogenic inhibitor activity. Active metalloprotease, which may be associated with various inflammatory processes as well as development of cancer cachexia. May play a critical role in follicular rupture. {ECO:0000250, ECO:0000269|PubMed:10438512}.;

Recessive Scores

pRec: 0.165

Intolerance Scores

LoFtool: 0.398
RVIS EVS: 0.07
RVIS percentile EVS: 59.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.829

Gene Damage Prediction

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