USP3

Summary

USP3 (ubiquitin specific peptidase 3, HGNC:12626) is a protein-coding gene on chromosome 15q22.31, encoding Ubiquitin carboxyl-terminal hydrolase 3 (Q9Y6I4). Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity.

Enables deubiquitinase activity and histone binding activity. Involved in DNA repair and DNA repair-dependent chromatin remodeling. Located in several cellular components, including Flemming body; cytoplasmic ribonucleoprotein granule; and nucleoplasm.

Source: NCBI Gene 9960 — RefSeq curated summary.

At a glance

• GWAS associations: 43
• Clinical variants (ClinVar): 61 total
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_006537

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12626
Approved symbol	USP3
Name	ubiquitin specific peptidase 3
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000140455
Ensembl biotype	protein_coding
OMIM	604728
Entrez	9960

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 16 protein_coding, 7 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000268049, ENST00000380324, ENST00000538686, ENST00000540797, ENST00000557884, ENST00000558157, ENST00000558218, ENST00000558285, ENST00000558925, ENST00000559192, ENST00000559257, ENST00000559276, ENST00000559711, ENST00000559718, ENST00000559771, ENST00000559873, ENST00000560070, ENST00000560202, ENST00000561326, ENST00000561381, ENST00000561442, ENST00000875483, ENST00000875484, ENST00000969958, ENST00000969959, ENST00000969960, ENST00000969961, ENST00000969962

RefSeq mRNA: 2 — MANE Select: NM_006537 NM_001256702, NM_006537

CCDS: CCDS32265, CCDS58370

Canonical transcript exons

ENST00000380324 — 15 exons

Exon	Start	End
ENSE00001342182	63504593	63504830
ENSE00003473619	63574323	63574403
ENSE00003487983	63553715	63553798
ENSE00003501637	63537025	63537156
ENSE00003530593	63588944	63589011
ENSE00003536568	63588305	63588423
ENSE00003567269	63574046	63574152
ENSE00003591322	63590661	63594633
ENSE00003603241	63562895	63563008
ENSE00003605842	63570433	63570579
ENSE00003620731	63532647	63532707
ENSE00003621011	63558106	63558188
ENSE00003623619	63556667	63556748
ENSE00003639723	63559857	63559970
ENSE00003660867	63588702	63588815

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.6416 / max 490.2392, expressed in 1822 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147141	35.7881	1821
147142	2.7653	1315
147140	1.3673	548
147143	0.8605	464
147146	0.2888	102
147144	0.2172	72
147139	0.2054	80
207561	0.1490	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.92	gold quality
mononuclear cell	CL:0000842	96.90	gold quality
leukocyte	CL:0000738	96.80	gold quality
sperm	CL:0000019	96.71	gold quality
ganglionic eminence	UBERON:0004023	96.41	gold quality
blood	UBERON:0000178	96.39	gold quality
bone marrow	UBERON:0002371	95.82	gold quality
bone marrow cell	CL:0002092	95.53	gold quality
granulocyte	CL:0000094	95.19	gold quality
palpebral conjunctiva	UBERON:0001812	95.17	gold quality
cerebellar cortex	UBERON:0002129	94.83	gold quality
cerebellar hemisphere	UBERON:0002245	94.83	gold quality
cortical plate	UBERON:0005343	94.74	gold quality
bone element	UBERON:0001474	94.54	gold quality
body of pancreas	UBERON:0001150	94.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.28	gold quality
cerebellum	UBERON:0002037	94.23	gold quality
embryo	UBERON:0000922	93.98	gold quality
cervix squamous epithelium	UBERON:0006922	93.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.71	gold quality
pancreatic ductal cell	CL:0002079	93.52	silver quality
upper leg skin	UBERON:0004262	93.34	gold quality
parotid gland	UBERON:0001831	93.27	gold quality
epithelium of nasopharynx	UBERON:0001951	92.97	gold quality
nasopharynx	UBERON:0001728	92.95	gold quality
amniotic fluid	UBERON:0000173	92.74	gold quality
tonsil	UBERON:0002372	92.73	gold quality
spleen	UBERON:0002106	92.69	gold quality
pancreas	UBERON:0001264	92.67	gold quality
male germ cell	CL:0000015	92.65	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	17.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

214 targeting USP3, 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-3163	100.00	77.23	8605
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10527-5P	99.91	72.28	3754

Literature-anchored findings (GeneRIF, showing 25)

• Ubiquitin-specific protease 3 (USP3) is a deubiquitinating enzyme for monoubiquitinated histones H2A and H2B; USP3 dynamically associates with chromatin and deubiquitinates H2A/H2B in vivo. (PMID:17980597)
• the role of UCP3 gene in functional status and survival at old age. (PMID:22743239)
• Taken together, the results suggested that USP3 is a negative regulator of ubiquitination signaling, counteracting RNF168- and RNF8-mediated ubiquitination. (PMID:24196443)
• as a direct target of miR-224, USP3 is a potent ceRNA of SMAD4 in CRC. Decreased expression of USP3 mRNA is associated with a poor prognosis and distal metastasis of CRC, which is attributed to further suppression of SMAD4 through the release of miR-224 from the USP3 3’UTR. (PMID:28655924)
• Depletion of USP3 lead to accelerated degradation of p53 in normal cells thereby enhanced cell proliferation and transformation. Reconstitution of wildtype USP3, but not the USP3 C168S mutant, restored the stability of p53 protein and inhibited cell proliferation and transformation. (PMID:28807825)
• Data found that USP3 was overexpressed in gastric cancer (GC) tissues and cells. USP3 overexpression can be a useful biomarker for predicting the outcomes of GC patients. Moreover, USP3 was shown to influence cell proliferation by regulating cell cycle control and metastasis-related proteins. In vivo experiments showed that USP3 promoted GC tumor growth and metastasis. (PMID:30168892)
• study mechanistically links USP3 to TRAF6 in osteoarthritis development; moreover, data support the pursuit of USP3 and TRAF6 as potential targets for osteoarthritis therapies (PMID:31056254)
• SUZ12 is indispensable for USP3-mediated oncogenic activity in gastric cancer . (PMID:31234902)
• USP3 is a new KLF5 deubiquitinase and that USP3 may represent a potential therapeutic target for breast cancer. (PMID:31624151)
• Smoothened Promotes Glioblastoma Radiation Resistance Via Activating USP3-Mediated Claspin Deubiquitination. (PMID:31900278)
• USP3 promotes proliferation of non-small cell lung cancer through regulating RBM4. (PMID:32271432)
• Upregulation of USP3 or downregulation of miR-224-5p restored proliferation and migration by MKN-28 and MGC-803 cells after hsa_circ_0017639 silencing. Upregulation of USP3 restored MKN-28 and MGC-803 cell proliferation and migration after overexpression of miR-224-5p. (PMID:32376451)
• Genome-scale screening of deubiquitinase subfamily identifies USP3 as a stabilizer of Cdc25A regulating cell cycle in cancer. (PMID:32415280)
• LncRNA HOXA-AS3 promotes the malignancy of glioblastoma through regulating miR-455-5p/USP3 axis. (PMID:32918360)
• An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability. (PMID:33767157)
• Ubiquitin-Specific Protease 3 Deubiquitinates and Stabilizes Oct4 Protein in Human Embryonic Stem Cells. (PMID:34070420)
• Protein deubiquitylase USP3 stabilizes Aurora A to promote proliferation and metastasis of esophageal squamous cell carcinoma. (PMID:34758762)
• MicroRNA-146-5p Promotes Pulmonary Artery Endothelial Cell Proliferation under Hypoxic Conditions through Regulating USP3. (PMID:34917199)
• USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation. (PMID:34930901)
• Deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners. (PMID:36574218)
• CRISPR/Cas9-based genome-wide screening of the deubiquitinase subfamily identifies USP3 as a protein stabilizer of REST blocking neuronal differentiation and promotes neuroblastoma tumorigenesis. (PMID:37170124)
• USP3 inhibition is Active Against Chemo-resistant Hepatocellular Carcinoma Anchorage-independent Growth via Suppressing Wnt/beta-catenin. (PMID:37921189)
• USP3 promotes cisplatin resistance in non-small cell lung cancer cells by suppressing ACOT7-regulated ferroptosis. (PMID:38502867)
• USP3 promotes osteosarcoma progression via deubiquitinating EPHA2 and activating the PI3K/AKT signaling pathway. (PMID:38531846)
• USP3: Key deubiquitylation enzyme in human diseases. (PMID:38651282)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp3	ENSDARG00000045641
mus_musculus	Usp3	ENSMUSG00000032376
rattus_norvegicus	Usp3	ENSRNOG00000017714

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 3 — Q9Y6I4 (reviewed: Q9Y6I4)

Alternative names: Deubiquitinating enzyme 3, Ubiquitin thioesterase 3, Ubiquitin-specific-processing protease 3

All UniProt accessions (13): Q9Y6I4, H0YKU8, H0YL81, H0YLB7, H0YLG0, H0YLJ0, H0YM72, H0YMI4, H0YMP6, H0YMW1, H0YNK1, H0YNX9, Q6JHV3

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity. In response to DNA damage, deubiquitinates monoubiquitinated target proteins such as histone H2A and H2AX and thereby counteracts RNF168- and RNF8-mediated ubiquitination. In turn, participates in the recruitment of DNA damage repair factors to DNA break sites. Required for proper progression through S phase and subsequent mitotic entry. Acts as a positive regulator of TP53 by deubiquitinating and stabilizing it to promote normal cell proliferation and transformation. Participates in establishing tolerance innate immune memory through non-transcriptional feedback. Mechanistically, negatively regulates TLR-induced NF-kappa-B signaling by targeting and removing the ‘Lys-63’-linked polyubiquitin chains on MYD88. Negatively regulates the activation of type I interferon signaling by mediating ‘Lys-63’-linked polyubiquitin chains on RIGI and IFIH1. Also deubiquitinates ASC/PYCARD, the central adapter mediating the assembly and activation of most inflammasomes, and thereby promotes inflammasome activation.

Subunit / interactions. Interacts (via UBP-type domain) with H2A; the interaction is less efficient than with monoubiquitinated H2A.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in all tissues examined, with strongest expression in pancreas.

Domain organisation. Both protease activity and an intact zinc finger are required for H2A monodeubiquitination.

Similarity. Belongs to the peptidase C19 family. USP3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y6I4-1	1	yes
Q9Y6I4-2	2

RefSeq proteins (2): NP_001243631, NP_006528* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR001607	Znf_UBP	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF02148

UniProt features (24 total): binding site 12, mutagenesis site 2, sequence conflict 2, active site 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6I4-F1	79.40	0.48

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 (2): 168 (nucleophile); 471 (proton acceptor)

Ligand- & substrate-binding residues (12): 44; 49; 56; 60; 82; 95; 98; 3; 5; 29; 32; 41

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (2):

Position	Phenotype
56	complete loss of deubiquitinase activity.
168	complete loss of deubiquitinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 332 (showing top): TAATAAT_MIR126, GNF2_BNIP2, TGCACTT_MIR519C_MIR519B_MIR519A, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, CAFFAREL_RESPONSE_TO_THC_UP, TGACCTY_ERR1_Q2, HNF1_Q6, FOXO1_01, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, CAGCTG_AP4_Q5, YGACNNYACAR_UNKNOWN, AP1_Q4_01, GNF2_MCL1, MYOD_01, RGTTAMWNATT_HNF1_01

GO Biological Process (6): DNA repair (GO:0006281), proteolysis (GO:0006508), protein deubiquitination (GO:0016579), DNA repair-dependent chromatin remodeling (GO:0140861), chromatin organization (GO:0006325), DNA damage response (GO:0006974)

GO Molecular Function (9): cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), histone binding (GO:0042393), histone H2B deubiquitinase activity (GO:0140936), histone H2A deubiquitinase activity (GO:0140950), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoplasmic ribonucleoprotein granule (GO:0036464), Flemming body (GO:0090543)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA damage response	2
histone deubiquitinase activity	2
DNA metabolic process	1
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
chromatin remodeling	1
cellular component organization	1
cellular response to stress	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
protein binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
ribonucleoprotein granule	1
midbody	1

Protein interactions and networks

STRING

1440 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP3	ZUP1	Q96AP4	660
USP3	OTUB1	Q96FW1	624
USP3	MYSM1	Q5VVJ2	621
USP3	BRCC3	P46736	615
USP3	RNF168	Q8IYW5	606
USP3	RIGI	O95786	602
USP3	CYLD	Q9NQC7	589
USP3	RNF8	O76064	577
USP3	IFIH1	Q9BYX4	570
USP3	OTUB2	Q96DC9	544
USP3	USP11	P51784	541
USP3	RNF135	Q8IUD6	523
USP3	OTUD5	Q96G74	519
USP3	H2AC20	Q16777	507
USP3	H2AC19	P20670	507

IntAct

16 interactions, top by confidence:

A	B	Type	Score
NT5E	SCAMP1	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
AURKA	CCNB2	psi-mi:“MI:0915”(physical association)	0.400
USP3	PDZK1P1	psi-mi:“MI:0915”(physical association)	0.400
ISLR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
GPC1	ATP2B4	psi-mi:“MI:0914”(association)	0.350
USP3	EIF3F	psi-mi:“MI:0914”(association)	0.350
NT5E	SCAMP3	psi-mi:“MI:0914”(association)	0.350
USP3	PDZK1	psi-mi:“MI:0914”(association)	0.350
ISLR		psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
MAGEA10	KANSL1L	psi-mi:“MI:0914”(association)	0.350
SPNS1	ACADS	psi-mi:“MI:0914”(association)	0.350
TP53BP1	PSMD14	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (112): HIST1H2AB (Affinity Capture-Western), HIST1H2BB (Affinity Capture-Western), USP3 (Affinity Capture-MS), RSU1 (Co-fractionation), USP3 (Co-fractionation), USP3 (Proximity Label-MS), TMEM173 (Affinity Capture-Western), USP3 (Affinity Capture-MS), USP3 (Affinity Capture-MS), USP3 (Affinity Capture-MS), PDZK1 (Affinity Capture-MS), USP3 (Reconstituted Complex), TP53 (Affinity Capture-Western), USP3 (Affinity Capture-Western), TP53 (Biochemical Activity)

ESM2 similar proteins: A1A5G2, A4FUN7, A4IF63, A5WWB0, A6H8I0, A6NNY8, C0HB46, D2HBJ8, D3ZQG6, E1C1R4, F7H9X2, O24454, P0C8Z3, P15209, P24786, P34547, P42694, Q03351, Q0V9G5, Q16288, Q16620, Q504Q3, Q52KZ6, Q5DU02, Q5R7T2, Q5U252, Q5XGZ2, Q63604, Q6DCJ1, Q6DFV5, Q6GNI6, Q6IE70, Q6NTR6, Q6P9L4, Q70CQ1, Q70EL2, Q7ZUM8, Q8BGF7, Q8BY87, Q8CEG8

Diamond homologs: A0A0R4IB93, A0JM59, A1CIL1, A1CW53, A2XDG4, A3AF13, A5PN09, A6QNM7, A7Z056, B1WBD7, B2GUZ1, B8NSV5, D3ZJ96, F6Z5C0, O22207, O60079, O94966, Q0CT11, Q0E2F9, Q0VA64, Q13107, Q2HJE4, Q2UUG8, Q3UJD6, Q3V0C5, Q4VSI4, Q5I043, Q5R5Z6, Q5RCD3, Q5ZM45, Q60MK8, Q6A4J8, Q6J1Y9, Q6PAW2, Q6U7I1, Q6ZQ93, Q70CQ2, Q76LT8, Q7JKC3, Q84WU2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3278 predictions. Top by Δscore:

Variant	Effect	Δscore
15:63504827:AGCGG:A	donor_loss	1.0000
15:63504828:GCG:G	donor_gain	1.0000
15:63504831:G:GG	donor_gain	1.0000
15:63504831:G:T	donor_loss	1.0000
15:63504832:T:G	donor_loss	1.0000
15:63532645:A:AG	acceptor_gain	1.0000
15:63532646:G:GG	acceptor_gain	1.0000
15:63532646:GT:G	acceptor_gain	1.0000
15:63553713:A:AG	acceptor_gain	1.0000
15:63553714:G:GG	acceptor_gain	1.0000
15:63553794:GAAAA:G	donor_gain	1.0000
15:63553796:AAAG:A	donor_loss	1.0000
15:63553797:AA:A	donor_gain	1.0000
15:63553797:AAGT:A	donor_loss	1.0000
15:63553798:AGT:A	donor_loss	1.0000
15:63553799:G:A	donor_loss	1.0000
15:63553799:G:GG	donor_gain	1.0000
15:63553800:TA:T	donor_loss	1.0000
15:63553801:A:AG	donor_loss	1.0000
15:63556662:A:AG	acceptor_gain	1.0000
15:63556665:A:AG	acceptor_gain	1.0000
15:63556666:G:GG	acceptor_gain	1.0000
15:63556666:GCTCA:G	acceptor_gain	1.0000
15:63556744:TAAAT:T	donor_gain	1.0000
15:63556747:AT:A	donor_gain	1.0000
15:63556749:G:GG	donor_gain	1.0000
15:63559855:A:AG	acceptor_gain	1.0000
15:63559856:G:GG	acceptor_gain	1.0000
15:63570557:TCTGC:T	donor_gain	1.0000
15:63570576:GCAT:G	donor_gain	1.0000

AlphaMissense

3447 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:63504746:T:C	C3R	1.000
15:63504748:T:G	C3W	1.000
15:63504824:T:C	C29R	1.000
15:63504825:G:A	C29Y	1.000
15:63504826:C:G	C29W	1.000
15:63532649:T:A	C32S	1.000
15:63532649:T:C	C32R	1.000
15:63532650:G:A	C32Y	1.000
15:63532650:G:C	C32S	1.000
15:63532651:C:G	C32W	1.000
15:63532670:T:A	W39R	1.000
15:63532670:T:C	W39R	1.000
15:63532672:G:C	W39C	1.000
15:63532672:G:T	W39C	1.000
15:63532676:T:C	C41R	1.000
15:63532677:G:A	C41Y	1.000
15:63532678:T:G	C41W	1.000
15:63532700:T:A	C49S	1.000
15:63532700:T:C	C49R	1.000
15:63532701:G:A	C49Y	1.000
15:63532701:G:C	C49S	1.000
15:63532701:G:T	C49F	1.000
15:63532702:T:G	C49W	1.000
15:63532703:G:A	G50R	1.000
15:63532703:G:C	G50R	1.000
15:63532704:G:A	G50E	1.000
15:63532704:G:T	G50V	1.000
15:63532707:G:C	R51T	1.000
15:63532707:G:T	R51M	1.000
15:63537025:G:C	R51S	1.000

dbSNP variants (sampled 300 via entrez): RS1000017583 (15:63503080 A>G), RS1000019868 (15:63562935 T>C), RS1000026819 (15:63591677 A>G,T), RS1000027704 (15:63560288 T>C,G), RS1000055078 (15:63520784 A>G), RS1000055148 (15:63587253 G>C), RS1000132970 (15:63554173 A>G,T), RS1000133071 (15:63569656 A>T), RS1000194965 (15:63568907 T>A,C), RS1000216801 (15:63571162 A>G), RS1000263877 (15:63533170 G>A), RS1000280373 (15:63583058 G>C), RS1000333684 (15:63582868 G>C), RS1000367138 (15:63577960 C>T), RS1000395356 (15:63533262 C>G)

Disease associations

OMIM: gene MIM:604728 | disease phenotypes:

GenCC curated gene-disease

Mondo (3): neutropenia (MONDO:0001475), lymphopenia (MONDO:0003783), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (1): Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0001875	Decreased total neutrophil count
HP:0001888	Decreased total lymphocyte count
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST000675_6	Heart failure	1.000000e-08
GCST004611_204	High light scatter reticulocyte count	2.000000e-13
GCST004612_138	High light scatter reticulocyte percentage of red cells	4.000000e-12
GCST004622_132	Reticulocyte count	4.000000e-12
GCST004651_3	Aortic root size	5.000000e-08
GCST006061_136	Atrial fibrillation	6.000000e-09
GCST006061_99	Atrial fibrillation	6.000000e-09
GCST006288_333	Heel bone mineral density	1.000000e-06
GCST006288_439	Heel bone mineral density	1.000000e-08
GCST006586_36	Urinary albumin excretion	2.000000e-08
GCST006867_127	Type 2 diabetes	3.000000e-10
GCST006896_10	Free thyroxine concentration	4.000000e-08
GCST006979_926	Heel bone mineral density	2.000000e-24
GCST007430_58	Peak expiratory flow	9.000000e-06
GCST007431_25	Lung function (FEV1/FVC)	2.000000e-20
GCST007432_56	FEV1	3.000000e-06
GCST007656_8	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	1.000000e-12
GCST008790_49	Urinary albumin-to-creatinine ratio	9.000000e-09
GCST008794_2	Urinary albumin-to-creatinine ratio	7.000000e-09
GCST009379_205	Type 2 diabetes	5.000000e-10
GCST009640_49	Urinary albumin-to-creatinine ratio	4.000000e-10
GCST010146_33	Serum immune biomarker levels	4.000000e-15
GCST010244_66	Triglyceride levels	4.000000e-31
GCST010245_94	LDL cholesterol levels	2.000000e-08
GCST010796_580	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST011494_66	Daytime nap	8.000000e-07
GCST90002382_242	Eosinophil percentage of white cells	3.000000e-11
GCST90002405_338	Reticulocyte count	2.000000e-23
GCST90002406_387	Reticulocyte fraction of red cells	9.000000e-20
GCST90013407_196	Liver enzyme levels (gamma-glutamyl transferase)	1.000000e-27

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0009270	heel bone mineral density
EFO:0004285	albuminuria
EFO:0009718	peak expiratory flow
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004869	YKL40 measurement
EFO:0004872	inflammatory biomarker measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004327	electrocardiography
EFO:0007828	daytime rest measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D008231	Lymphopenia	C15.378.243.750.605; C15.378.553.546.605; C20.673.627
D009503	Neutropenia	C15.378.243.750.184.564; C15.378.553.546.184.564

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291515 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, decreases expression, affects expression	3
Valproic Acid	decreases expression, decreases methylation, increases expression	3
Cyclosporine	increases expression	3
trichostatin A	affects expression, increases expression	2
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
K 7174	increases expression	1
abrine	increases expression	1
Rosiglitazone	increases expression	1
Arsenic Trioxide	increases expression	1
Cidofovir	affects expression	1
Benzene	increases expression	1
Coumestrol	decreases expression, affects cotreatment	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Gallic Acid	increases expression	1
Ifosfamide	increases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Oxygen	increases expression	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1
Selenium	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228938	Binding	Binding affinity to biotinylated USP3 zinc finger ubiquitin binding domain (1 to 131 residues) (unknown origin) expressed in Escherichia coli incubated for 120 secs by Biolayer Interferometry assay	Structure-Activity Relationship of USP5 Inhibitors. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TW83	HAP1 USP3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00125723	PHASE4	COMPLETED	FIRST - Study of Pegfilgrastim Administered in the First and Subsequent Cycles of Myelosuppressive Chemotherapy
NCT00194857	PHASE4	TERMINATED	Treatment of Anemia and Neutropenia in HIV/HCV Coinfected Patients Treated With Pegylated Interferon and Ribavirin
NCT00257790	PHASE4	COMPLETED	The Tobramycin Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00686543	PHASE4	COMPLETED	Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01114165	PHASE4	COMPLETED	Value of the LightCycler® SeptiFast Test MGRADE for the Pathogen Detection in Neutropenic Hematological Patients
NCT01135589	PHASE4	UNKNOWN	Micafungin Prevention Study for Fungal Disease in Child Receiving Allogenic Hematopoietic Stem Cell Transplantation
NCT01571518	PHASE4	UNKNOWN	Prevention of Neutropenia After Using G-CSF With TAC Chemotherapy
NCT02621905	PHASE4	COMPLETED	Steady-State Comparative Bioavailability Study in Prophylaxis Patients of Lozanoc® 50 mg With Sporanox® 100 mg
NCT02967341	PHASE4	UNKNOWN	Blood Draw Validation for Ciprofloxacin Pharmacokinetic Research in Pediatric Cancer Patients
NCT04009941	PHASE4	COMPLETED	Efficacy and Safety of 4.5mg PEG-rhG-CSF Per Cycle in Preventing Neutropenia After Intensive Chemotherapy for Breast Cancer
NCT04904614	PHASE4	COMPLETED	Letermovir Use in Heart Transplant Recipients
NCT05626530	PHASE4	RECRUITING	Letermovir for Secondary Prophylaxis in Solid Organ Transplant Recipients
NCT06145321	PHASE4	ACTIVE_NOT_RECRUITING	Continuous Versus Bolus Administration of G-CSF in Children With Cancer
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00001338	PHASE3	COMPLETED	A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00002658	PHASE3	UNKNOWN	Combination Chemotherapy, Biological Therapy, and Bone Marrow Transplantation in Treating Patients With Acute Myeloid Leukemia
NCT00002719	PHASE3	COMPLETED	Combination Chemotherapy With or Without G-CSF in Treating Older Patients With Acute Myeloid Leukemia
NCT00003739	PHASE3	COMPLETED	Antibiotic Therapy With or Without G-CSF in Treating Children With Neutropenia and Fever Caused by Chemotherapy
NCT00020865	PHASE3	UNKNOWN	Levofloxacin Compared With Cefepime in Treating Cancer Patients With Fever and Neutropenia
NCT00035594	PHASE3	COMPLETED	Pegfilgrastim as Support to Advanced Breast Cancer Patients Receiving Chemotherapy
NCT00044486	PHASE3	COMPLETED	Prophylaxis Trial of Posaconazole Versus Standard Azole Therapy for Neutropenic Patients (Study P01899)
NCT00107081	PHASE3	TERMINATED	Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting
NCT00445497	PHASE3	UNKNOWN	Early Hospital Discharge or Standard Inpatient Care in Cancer Patients Receiving Antibiotics for Febrile Neutropenia
NCT00529282	PHASE3	TERMINATED	A Study of Ceftobiprole in Patients With Fever and Neutropenia.
NCT00627393	PHASE3	COMPLETED	Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
NCT00770172	PHASE3	COMPLETED	G-CSF in Preventing Neutropenia in Patients With Solid Tumors Who Are Receiving Chemotherapy
NCT00784368	PHASE3	COMPLETED	A Pharmacokinetic Study of JK1211(Itraconazole [Itrizole]) Oral Solution in Participants With Deep Mycosis and Those With Febrile Neutropenia Suspected of Fungal Infection
NCT00806351	PHASE3	TERMINATED	An Evaluation Of The Effectiveness And Safety Of Anidulafungin Compared To Caspofungin For The Treatment Of Serious Fungal Infection Due To Candida In Patients With A Dysfunctional Immune System
NCT00911170	PHASE3	COMPLETED	PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study