USP20

protein-coding

ubiquitin specific peptidase 20, the group of Ubiquitin specific peptidases|MicroRNA protein coding host genes

Gene summary

This gene encodes a ubiquitin specific processing protease that was first identified as a substrate of the VHL (von Hippel-Lindau disease) protein E3 ubiquitin ligase complex. In addition to being ubiquitinated by the VHL-E3 ligase complex, this enzyme deubiquitinates hypoxia-inducible factor (HIF)-1 alpha and thereby causes increased expression of HIF-1alpha targeted genes which play a role in angiogenesis, glucose metabolism, cell proliferation and metastasis. The enzyme encoded by this gene also regulates G-protein coupled receptor signaling by mediating the deubiquitination of beta-2 adrenergic receptor (ADRB2). This enzyme is a ubiquitously expressed thiolester hydrolase. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jan 2013]

MANE transcript

NM_001110303.4

Inheritance

—

ClinVar variants

U:170B:10

Top phenotype

EBV-positive nodal T- and NK-cell lymphoma

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr9:129,834,698-129,881,828

External References & Databases

Ensembl (ENSG00000136878)

Transcript & Mutation Effects

hg38 • Region Span ~47.1 kb

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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 USP20 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 150

not providedTotal: 8

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001110303.4. 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	1 clinvar	5 clinvar	11
missense			156 clinvar	2 clinvar	1 clinvar	159
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar	1 clinvar		2
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	170	4	6	180

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001110303.4	RefSeq	NP_001103773.2	23	MANE Select
ENST00000372429.8	Ensembl	ENSP00000361506.3	23	MANE Select
NM_001008563.5	RefSeq	NP_001008563.2	23	Standard
NM_006676.8	RefSeq	NP_006667.3	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
usp20	Danio rerio	Structure: pharyngeal arch cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

usp20

Danio rerio

Structure: pharyngeal arch cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Ub-specific processing proteases
Deubiquitination

Biological Process

ubiquitin-dependent protein catabolic process
endocytosis
regulation of G protein-coupled receptor signaling pathway
protein deubiquitination
protein K63-linked deubiquitination

Molecular Function

G protein-coupled receptor binding
cysteine-type endopeptidase activity
thiol-dependent ubiquitin-specific protease activity
protein binding
zinc ion binding

Cellular Component

cytoplasm
centrosome
cytosol
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315480
Coding exons: 23
Length: 47131
Individuals with no LoFs: 124778
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 124822
p: 0.000176

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.43	502	601	0.836	0.0000409	5946
Missense (PolyPhen)		149	209.99	0.70955		2142
Synonymous	0.535	250	261	0.958	0.0000198	1767
Loss of Function	4.66	18	55.4	0.325	0.00000288	586

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00045	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00028	0.00028	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00021	0.00019	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinating enzyme involved in beta-2 adrenergic receptor (ADRB2) recycling. Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination beta-2 adrenergic receptor (ADRB2). Plays a central role in ADRB2 recycling and resensitization after prolonged agonist stimulation by constitutively binding ADRB2, mediating deubiquitination of ADRB2 and inhibiting lysosomal trafficking of ADRB2. Upon dissociation, it is probably transferred to the translocated beta-arrestins, possibly leading to beta-arrestins deubiquitination and disengagement from ADRB2. This suggests the existence of a dynamic exchange between the ADRB2 and beta-arrestins. Deubiquitinates DIO2, thereby regulating thyroid hormone regulation. Deubiquitinates HIF1A, leading to stabilize HIF1A and enhance HIF1A-mediated activity. Mediates deubiquitination of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. {ECO:0000269|PubMed:12056827, ECO:0000269|PubMed:12865408, ECO:0000269|PubMed:15776016, ECO:0000269|PubMed:19424180}.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.754
RVIS EVS: -0.37
RVIS percentile EVS: 28.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.927

Gene Damage Prediction

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