ADAMTS3

Summary

ADAMTS3 (ADAM metallopeptidase with thrombospondin type 1 motif 3, HGNC:219) is a protein-coding gene on chromosome 4q13.3, encoding A disintegrin and metalloproteinase with thrombospondin motifs 3 (O15072). Cleaves the propeptides of type II collagen prior to fibril assembly.

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 protease. This protease, a member of the procollagen aminopropeptidase subfamily of proteins, may play a role in the processing of type II fibrillar collagen in articular cartilage.

Source: NCBI Gene 9508 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hennekam lymphangiectasia-lymphedema syndrome 3 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 71
• Clinical variants (ClinVar): 249 total — 14 pathogenic
• Phenotypes (HPO): 63
• MANE Select transcript: NM_014243

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:219
Approved symbol	ADAMTS3
Name	ADAM metallopeptidase with thrombospondin type 1 motif 3
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0366, ADAMTS-4
Ensembl gene	ENSG00000156140
Ensembl biotype	protein_coding
OMIM	605011
Entrez	9508

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000286657, ENST00000505193, ENST00000511274

RefSeq mRNA: 1 — MANE Select: NM_014243 NM_014243

CCDS: CCDS3553

Canonical transcript exons

ENST00000286657 — 22 exons

Exon	Start	End
ENSE00001024777	72312291	72312466
ENSE00001024779	72295654	72295786
ENSE00001024783	72315858	72315971
ENSE00001024785	72288751	72288868
ENSE00001024787	72339494	72339693
ENSE00001024788	72298277	72298442
ENSE00001024789	72290855	72291062
ENSE00001024790	72319332	72319475
ENSE00001024791	72313677	72313822
ENSE00001024792	72414815	72414971
ENSE00001024795	72318572	72318704
ENSE00001024797	72320714	72320870
ENSE00001138536	72280969	72283704
ENSE00001178422	72568694	72569221
ENSE00002450503	72323014	72323097
ENSE00002526278	72319858	72319963
ENSE00003516498	72548478	72548884
ENSE00003538284	72567374	72567401
ENSE00003565187	72311048	72311181
ENSE00003577289	72303917	72304080
ENSE00003617278	72305987	72306067
ENSE00003693232	72309397	72309520

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 88.24.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0017 / max 295.8473, expressed in 827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52461	1.6474	484
52460	1.3131	655
52459	0.0413	8

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	88.24	gold quality
cartilage tissue	UBERON:0002418	83.82	gold quality
periodontal ligament	UBERON:0008266	83.40	gold quality
parietal pleura	UBERON:0002400	80.90	gold quality
germinal epithelium of ovary	UBERON:0001304	79.74	gold quality
tibia	UBERON:0000979	78.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.05	gold quality
adrenal tissue	UBERON:0018303	76.50	gold quality
pleura	UBERON:0000977	76.27	gold quality
cortical plate	UBERON:0005343	75.34	gold quality
caput epididymis	UBERON:0004358	74.34	gold quality
secondary oocyte	CL:0000655	72.73	gold quality
left uterine tube	UBERON:0001303	72.20	gold quality
middle temporal gyrus	UBERON:0002771	71.30	gold quality
calcaneal tendon	UBERON:0003701	69.48	gold quality
corpus epididymis	UBERON:0004359	69.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.91	gold quality
ovary	UBERON:0000992	68.11	gold quality
visceral pleura	UBERON:0002401	68.11	gold quality
omental fat pad	UBERON:0010414	67.55	gold quality
peritoneum	UBERON:0002358	67.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	67.30	silver quality
cauda epididymis	UBERON:0004360	67.19	gold quality
left ovary	UBERON:0002119	66.75	gold quality
adipose tissue of abdominal region	UBERON:0007808	66.08	gold quality
right ovary	UBERON:0002118	65.75	gold quality
smooth muscle tissue	UBERON:0001135	65.73	gold quality
prefrontal cortex	UBERON:0000451	65.57	gold quality
buccal mucosa cell	CL:0002336	65.44	gold quality
pericardium	UBERON:0002407	65.36	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	9.87
E-ANND-3	no	5.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

191 targeting ADAMTS3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955

Literature-anchored findings (GeneRIF, showing 9)

• extracellular matrix degrading enzyme (PMID:11831030)
• ADAMTS-2, -3, and -13 expression, but not that of ADAMTS-14, are increased in plaques causing AMI compared those associated with stable angina. (PMID:22205175)
• Data indicate that ADAMTS2 and 3 cleave the amino-propeptide of fibrillar collagens and regulate blood vessels homeostasis and lymphangiogenesis. [review] (PMID:25863161)
• The pregnancy loss rate seems to be affected by both ADAMTS-3 and ADAMTS-16. (PMID:28088271)
• Findings suggest that these MMP16 rs10090371, ADAMTS3 rs788935, TLL2 rs10882807 and MMP9 rs3918251 may be promising prognostic biomarkers for cutaneous melanoma specific survival (CMSS). (PMID:28796414)
• Results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells. (PMID:28985353)
• Molecular cloning and in silico analysis identify potential transcription factor binding sites in the ADAMTS3 promoter region and show that SP1 downregulated ADAMTS3 transcriptional activity in osteosarcoma cell lines. As consistent with the transcriptional activity, mRNA, and protein expression levels were also decreased by SP1. (PMID:29518549)
• There is report of one family supporting mutations in ADAMTS3 as causative for the phenotype labeled as HKLLS3. Here, we report an additional case of HKLLS that appears to be associated with homozygous nonsense mutation of ADAMTS3. (PMID:30450763)
• ADAMTS3 restricts cancer invasion in models of early breast cancer progression through enhanced fibronectin degradation. (PMID:37336268)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts3	ENSDARG00000060127
mus_musculus	Adamts3	ENSMUSG00000043635
rattus_norvegicus	Adamts3	ENSRNOG00000027463

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), ADAMTS10 (ENSG00000142303), ADAMTSL4 (ENSG00000143382), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS13 (ENSG00000160323), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 3 — O15072 (reviewed: O15072)

Alternative names: Procollagen II N-proteinase, Procollagen II amino propeptide-processing enzyme

All UniProt accessions (1): O15072

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the propeptides of type II collagen prior to fibril assembly. Does not act on types I and III collagens.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Found in cartilage and skin.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion.

Disease relevance. Hennekam lymphangiectasia-lymphedema syndrome 3 (HKLLS3) [MIM:618154] A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and some manifest intellectual disability. HKLLS3 is characterized by widespread congenital edema, facial dysmorphism and protein-losing enteropathy of variable severity. HKLLS3 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix.

RefSeq proteins (1): NP_055058* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR010909	PLAC	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR041645	ADAMTS_CR_2	Domain
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF01421, PF01562, PF05986, PF17771, PF19030, PF19236

Enzyme classification (BRENDA):

• EC 3.4.24.14 — procollagen N-endopeptidase (BRENDA: 10 organisms, 94 substrates, 74 inhibitors, 17 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROCOLLAGEN I	—	12
PNCOLLAGEN, CARBOXYMETHYLATED	0.0028	1
PROCOLLAGEN II	0.0002	1
PROPEPTIDE OF COLLAGEN ALPHA-1 CHAIN	0.001	1
PROPEPTIDE OF COLLAGEN ALPHA-2 CHAIN	0.001	1

UniProt features (42 total): disulfide bond 13, glycosylation site 7, domain 7, sequence variant 4, binding site 3, region of interest 2, signal peptide 1, propeptide 1, compositionally biased region 1, active site 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15072-F1	71.31	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 399

Ligand- & substrate-binding residues (3): 398; 402; 408

Disulfide bonds (13): 333–382, 376–455, 415–441, 482–507, 493–516, 502–535, 529–540, 563–600, 567–605, 578–590, 978–1010, 982–1015, 993–999

Glycosylation sites (7): 83, 119, 242, 345, 475, 814, 942

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1474244	Extracellular matrix organization
R-HSA-1474290	Collagen formation
R-HSA-1643685	Disease
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 370 (showing top): RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOMF_METALLOPEPTIDASE_ACTIVITY, MODULE_255, SP3_Q3, ATACCTC_MIR202, BROWNE_HCMV_INFECTION_16HR_UP, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, chr4q13, EVI1_05, GOBP_PROTEIN_MATURATION, ATF1_Q6

GO Biological Process (10): in utero embryonic development (GO:0001701), proteolysis (GO:0006508), vascular endothelial growth factor production (GO:0010573), protein processing (GO:0016485), extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), collagen catabolic process (GO:0030574), collagen biosynthetic process (GO:0032964), supramolecular fiber organization (GO:0097435), positive regulation of vascular endothelial growth factor signaling pathway (GO:1900748)

GO Molecular Function (9): endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), heparin binding (GO:0008201), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Collagen formation	1
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Extracellular matrix organization	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
collagen metabolic process	2
peptidase activity	2
chordate embryonic development	1
protein metabolic process	1
cytokine production	1
proteolysis	1
protein maturation	1
extracellular structure organization	1
external encapsulating structure organization	1
extracellular matrix organization	1
catabolic process	1
biosynthetic process	1
cellular component organization	1
positive regulation of signal transduction	1
vascular endothelial growth factor signaling pathway	1
regulation of vascular endothelial growth factor signaling pathway	1
endopeptidase activity	1
metallopeptidase activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1
external encapsulating structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS3	ACAN	P16112	961
ADAMTS3	MMP13	P45452	901
ADAMTS3	MMP3	P08254	864
ADAMTS3	CCBE1	Q6UXH8	825
ADAMTS3	FURIN	P09958	765
ADAMTS3	MMP1	P03956	751
ADAMTS3	TIMP1	P01033	733
ADAMTS3	COL10A1	Q03692	730
ADAMTS3	FN1	P02751	713
ADAMTS3	COL2A1	P02458	698
ADAMTS3	FBLN1	P23142	670
ADAMTS3	IL1B	P01584	662
ADAMTS3	MMP14	P50281	629
ADAMTS3	TIMP3	P35625	619
ADAMTS3	MMP9	P14780	612

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ADAMTS3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
ADAMTS3	HSP90B1	psi-mi:“MI:0915”(physical association)	0.400
ADAMTS3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): ADAMTS3 (Affinity Capture-RNA), UBQLN2 (Two-hybrid), HSP90B1 (Proximity Label-MS), ADAMTS3 (Proximity Label-MS), ADAMTS3 (Proximity Label-MS), ADAMTS3 (Proximity Label-MS), ADAMTS3 (Proximity Label-MS), GALK1 (Co-fractionation), MAT1A (Co-fractionation), MAT2A (Co-fractionation), NDUFS8 (Co-fractionation), NDUFV2 (Co-fractionation), ADAMTS3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0N9E2K8, A0A1D5NSK0, A0A8M9PFP2, G5ECS8, G5EFD9, O15072, O18767, O43909, O60882, O62806, O77656, O93470, P07152, P22003, P23097, P28825, P29788, P33435, P49003, P57748, P79287, Q10835, Q11005, Q14703, Q16819, Q16820, Q19791, Q24025, Q3U435, Q568B8, Q61847, Q64230, Q6GQB9, Q6NP60, Q8CGD2, Q8K3F2, Q8N119, Q8R4K8, Q8VDA1, Q90YC2

Diamond homologs: A2VEC9, A6QNY1, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, O08721, O08722, O08747, O14514, O15072, O55225, O60241, O60242, O75173, O88783, O95185, O95450, P04275, P07358, P07996, P27918, P35441, P35442, P35448, P55314, P57110, P58397, P58459, P59384, P79331, P80012, P97857, P98088, P98092, P98160, P98164

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

249 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	0
Uncertain significance	179
Likely benign	29
Benign	16

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1527090	GRCh37/hg19 4q13.1-13.3(chr4:61867555-74711517)	Pathogenic
1527095	GRCh37/hg19 4q13.3-21.21(chr4:73055313-80083154)	Pathogenic
2685114	GRCh37/hg19 4q13.2-13.3(chr4:69146217-75500577)x1	Pathogenic
4081950	NC_000004.12:g.72031892_78939234del	Pathogenic
443262	GRCh37/hg19 4q13.1-21.1(chr4:66017575-76772947)x1	Pathogenic
4796371	GRCh38/hg38 4q13.2-21.1(chr4:67406178-76619632)x1	Pathogenic
562920	GRCh37/hg19 4q13.1-13.3(chr4:64705501-73469716)x3	Pathogenic
58031	GRCh38/hg38 4q13.3-21.21(chr4:71128874-78099088)x3	Pathogenic
586987	NM_014243.3(ADAMTS3):c.503T>C (p.Leu168Pro)	Pathogenic
586988	NM_014243.3(ADAMTS3):c.872T>C (p.Ile291Thr)	Pathogenic
59451	GRCh38/hg38 4q13.1-13.3(chr4:65454562-72313693)x1	Pathogenic
627548	NM_014243.3(ADAMTS3):c.280C>T (p.Arg94Ter)	Pathogenic
685236	GRCh37/hg19 4q13.2-21.22(chr4:68242784-82991431)x3	Pathogenic
814563	GRCh37/hg19 4q13.2-21.21(chr4:68950363-79738598)x1	Pathogenic

SpliceAI

4996 predictions. Top by Δscore:

Variant	Effect	Δscore
4:72288746:CCTA:C	donor_loss	1.0000
4:72288747:CTAC:C	donor_loss	1.0000
4:72288748:TA:T	donor_loss	1.0000
4:72288749:A:AC	donor_gain	1.0000
4:72288750:C:CC	donor_gain	1.0000
4:72288864:GAACA:G	acceptor_gain	1.0000
4:72288865:AACA:A	acceptor_gain	1.0000
4:72288866:ACA:A	acceptor_gain	1.0000
4:72288867:CA:C	acceptor_gain	1.0000
4:72288867:CAC:C	acceptor_gain	1.0000
4:72288868:AC:A	acceptor_loss	1.0000
4:72288869:C:CA	acceptor_loss	1.0000
4:72288869:C:CC	acceptor_gain	1.0000
4:72295652:A:AC	donor_gain	1.0000
4:72295653:C:CT	donor_gain	1.0000
4:72295653:CA:C	donor_gain	1.0000
4:72295653:CAG:C	donor_gain	1.0000
4:72295653:CAGTG:C	donor_gain	1.0000
4:72303912:CATA:C	donor_loss	1.0000
4:72303913:ATAC:A	donor_loss	1.0000
4:72303914:TACC:T	donor_loss	1.0000
4:72303916:C:CA	donor_loss	1.0000
4:72304078:TAG:T	acceptor_gain	1.0000
4:72304079:AGC:A	acceptor_loss	1.0000
4:72304080:GCTAA:G	acceptor_loss	1.0000
4:72304081:C:CA	acceptor_loss	1.0000
4:72304081:C:CC	acceptor_gain	1.0000
4:72306088:T:C	acceptor_gain	1.0000
4:72306088:T:TC	acceptor_gain	1.0000
4:72306098:C:CT	acceptor_gain	1.0000

AlphaMissense

8000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:72291044:C:A	W914C	1.000
4:72291044:C:G	W914C	1.000
4:72298305:C:A	W854C	1.000
4:72298305:C:G	W854C	1.000
4:72298320:C:A	W849C	1.000
4:72298320:C:G	W849C	1.000
4:72298322:A:G	W849R	1.000
4:72298322:A:T	W849R	1.000
4:72313817:G:C	C535W	1.000
4:72313818:C:G	C535S	1.000
4:72313819:A:G	C535R	1.000
4:72313819:A:T	C535S	1.000
4:72315870:A:C	C529W	1.000
4:72315871:C:G	C529S	1.000
4:72315872:A:G	C529R	1.000
4:72315872:A:T	C529S	1.000
4:72315880:C:A	G526V	1.000
4:72315880:C:T	G526E	1.000
4:72315881:C:A	G526W	1.000
4:72315900:T:A	K519N	1.000
4:72315900:T:G	K519N	1.000
4:72315909:A:C	C516W	1.000
4:72315910:C:A	C516F	1.000
4:72315910:C:G	C516S	1.000
4:72315910:C:T	C516Y	1.000
4:72315911:A:G	C516R	1.000
4:72315911:A:T	C516S	1.000
4:72315936:A:C	C507W	1.000
4:72315937:C:G	C507S	1.000
4:72315937:C:T	C507Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000008351 (4:72485382 T>C), RS1000009041 (4:72445423 T>C), RS1000023468 (4:72318452 A>G), RS1000038175 (4:72368403 G>A), RS1000043246 (4:72545284 T>A,C), RS1000079712 (4:72563942 A>G), RS1000087738 (4:72496688 G>C), RS1000087843 (4:72404315 AACAG>A), RS1000089056 (4:72280910 A>G), RS1000096094 (4:72500463 T>A), RS1000097347 (4:72325288 T>C), RS1000102692 (4:72421663 T>G), RS1000117936 (4:72547680 A>G), RS10001463 (4:72417688 T>A,G), RS1000149250 (4:72491616 A>T)

Disease associations

OMIM: gene MIM:605011 | disease phenotypes: MIM:618154, MIM:619504

GenCC curated gene-disease

Disease	Classification	Inheritance
hennekam lymphangiectasia-lymphedema syndrome 3	Strong	Autosomal recessive
Hennekam syndrome	Supportive	Autosomal recessive

Mondo (4): hennekam lymphangiectasia-lymphedema syndrome 3 (MONDO:0032564), prostate cancer (MONDO:0008315), Chopra-Amiel-Gordon syndrome (MONDO:0859186), Hennekam syndrome (MONDO:0016256)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000034	Hydrocele testis
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000160	Narrow mouth
HP:0000212	Gingival overgrowth
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000405	Conductive hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0000684	Delayed eruption of teeth
HP:0000774	Narrow chest
HP:0001004	Lymphedema
HP:0001055	Erysipelas
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001302	Pachygyria
HP:0001363	Craniosynostosis
HP:0001530	Mild postnatal growth retardation
HP:0001541	Ascites

GWAS associations

71 associations (top):

Study	Trait	p-value
GCST000817_54	Height	2.000000e-14
GCST001066_3	Dialysis-related mortality	1.000000e-06
GCST001639_18	Metabolite levels	3.000000e-09
GCST001786_32	Dental caries	3.000000e-07
GCST001786_4	Dental caries	2.000000e-06
GCST002647_139	Height	5.000000e-24
GCST002702_48	Height	7.000000e-12
GCST002896_45	Cholesterol, total	2.000000e-09
GCST003336_10	Waist circumference adjusted for body mass index	9.000000e-08
GCST004067_120	Hip circumference adjusted for BMI	7.000000e-10
GCST004067_51	Hip circumference adjusted for BMI	1.000000e-07
GCST004500_137	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	5.000000e-19
GCST004501_2	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-19
GCST004504_22	Waist circumference adjusted for BMI in non-smokers	9.000000e-20
GCST004562_181	Waist circumference adjusted for body mass index	2.000000e-08
GCST004562_200	Waist circumference adjusted for body mass index	9.000000e-06
GCST004563_231	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	4.000000e-08
GCST004564_110	Waist circumference adjusted for BMI in active individuals	7.000000e-07
GCST005447_36	Total cholesterol levels in LDL	2.000000e-11
GCST005448_8	Serum total cholesterol levels	1.000000e-14
GCST005481_2	Large LDL particle concentration	3.000000e-08
GCST005483_3	Total cholesterol levels in large LDL	4.000000e-08
GCST005484_1	Cholesterol ester levels in large LDL	4.000000e-08
GCST005486_1	Medium LDL particle concentration	2.000000e-08
GCST005486_2	Medium LDL particle concentration	2.000000e-08
GCST005486_3	Medium LDL particle concentration	3.000000e-09
GCST005488_1	Total cholesterol levels in medium LDL	4.000000e-08
GCST005488_2	Total cholesterol levels in medium LDL	4.000000e-08
GCST005488_3	Total cholesterol levels in medium LDL	8.000000e-09
GCST005489_2	Cholesterol ester levels in medium LDL	3.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004574	total cholesterol measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0008589	esterified cholesterol measurement
EFO:0005035	hippocampal volume
EFO:0009767	glycine measurement
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
trichostatin A	affects cotreatment, increases expression	3
Vorinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
bisphenol F	affects cotreatment, decreases methylation	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
belinostat	decreases expression	1
abrine	increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Arbutin	decreases expression	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Nickel	increases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer