USP8

ubiquitin specific peptidase 8, the group of Ubiquitin specific peptidases

Basic information

Region (hg38): 15:50424379-50514421

Links

ENSG00000138592 ∙ NCBI:9101 ∙ OMIM:603158 ∙ HGNC:12631 ∙ Uniprot:P40818 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive spastic paraplegia type 59 (Supportive), mode of inheritance: AR
• developmental and epileptic encephalopathy (Limited), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the USP8 gene.

• Hereditary spastic paraplegia (112 variants)
• not provided (18 variants)
• - (2 variants)
• not specified (1 variants)
• USP8-related condition (1 variants)
• Pituitary dependent hypercortisolism (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the USP8 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				30	6	36
missense			50	3	12	65
nonsense	1		2			3
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	2	1	5
non coding				11	6	17
Total	1	0	53	44	24

Variants in USP8

This is a list of pathogenic ClinVar variants found in the USP8 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-50439016-G-C			Benign (Dec 16, 2020)
15-50439097-T-C			Likely benign (Apr 13, 2018)
15-50439109-C-T		Hereditary spastic paraplegia	Likely benign (Jun 24, 2023)
15-50439182-G-C		Hereditary spastic paraplegia	Uncertain significance (Nov 22, 2023)
15-50439193-C-T		Hereditary spastic paraplegia	Benign (Jan 31, 2024)
15-50439194-G-A		Hereditary spastic paraplegia	Likely benign (Aug 24, 2023)
15-50439197-A-G		Hereditary spastic paraplegia	Likely benign (Jul 13, 2023)
15-50441511-ATTG-A		Hereditary spastic paraplegia	Benign (Jun 24, 2023)
15-50449385-T-C		Hereditary spastic paraplegia	Likely benign (Dec 14, 2023)
15-50449392-A-C			Benign (Jun 08, 2017)
15-50449404-A-C		Hereditary spastic paraplegia	Uncertain significance (Jul 09, 2019)
15-50449418-C-T		Hereditary spastic paraplegia	Uncertain significance (Jul 05, 2022)
15-50449447-C-A		Hereditary spastic paraplegia	Likely benign (Dec 31, 2019)
15-50449447-C-T		Hereditary spastic paraplegia	Likely benign (Mar 29, 2023)
15-50449467-C-G		Hereditary spastic paraplegia	Uncertain significance (Mar 10, 2021)
15-50449489-C-G		Hereditary spastic paraplegia	Uncertain significance (May 23, 2022)
15-50449492-A-G		Hereditary spastic paraplegia	Uncertain significance (Jul 18, 2019)
15-50459061-C-T		Hereditary spastic paraplegia	Uncertain significance (Aug 30, 2021)
15-50459064-C-T		Hereditary spastic paraplegia	Benign (Dec 07, 2023)
15-50459143-C-G		Hereditary spastic paraplegia	Uncertain significance (Nov 01, 2022)
15-50459158-A-T		Hereditary spastic paraplegia	Uncertain significance (Oct 24, 2023)
15-50462267-T-C		Hereditary spastic paraplegia	Likely benign (Jan 27, 2024)
15-50462294-G-C		Hereditary spastic paraplegia	Uncertain significance (Dec 07, 2022)
15-50462296-A-G		Hereditary spastic paraplegia	Uncertain significance (Jan 01, 2022)
15-50462311-C-G		Hereditary spastic paraplegia	Uncertain significance (Nov 21, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
USP8	protein_coding	protein_coding	ENST00000433963	19	76704

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.57e-8	125722	0	9	125731	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.87	439	564	0.779	0.0000289	7316
Missense in Polyphen		188	299.06	0.62864		4036
Synonymous	1.00	176	194	0.908	0.00000951	2073
Loss of Function	6.66	2	55.6	0.0360	0.00000286	736

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000960	0.0000958
Ashkenazi Jewish	0.000114	0.0000992
East Asian	0.00	0.00
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000362	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000167	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, ECO:0000269|PubMed:9628861}.
• Disease: DISEASE: Pituitary adenoma 4, ACTH-secreting (PITA4) [MIM:219090]: A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete. PITA4 results in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:28505279}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cushing,s syndrome - Homo sapiens (human);Endocytosis - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);EGF-EGFR Signaling Pathway;Signaling by WNT;Signal Transduction;Post-translational protein modification;Metabolism of proteins;Regulation of FZD by ubiquitination;Downregulation of ERBB2:ERBB3 signaling;Downregulation of ERBB2 signaling;Ub-specific processing proteases;Deubiquitination;Signaling by ERBB2;Negative regulation of MET activity;Signaling by MET;Signaling by Receptor Tyrosine Kinases;ErbB2/ErbB3 signaling events;Internalization of ErbB1;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.121

Intolerance Scores

• loftool: 0.379
• rvis_EVS: 0.4
• rvis_percentile_EVS: 76.45

Haploinsufficiency Scores

• pHI: 0.216
• hipred: Y
• hipred_score: 0.831
• ghis: 0.546

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.603

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Usp8
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; liver/biliary system phenotype; embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: usp8
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: branched

Gene ontology

• Biological process: mitotic cytokinesis;ubiquitin-dependent protein catabolic process;endosome organization;Ras protein signal transduction;cell population proliferation;protein deubiquitination;regulation of protein stability;regulation of protein localization;protein K63-linked deubiquitination;protein K48-linked deubiquitination;cellular response to dexamethasone stimulus;positive regulation of canonical Wnt signaling pathway;regulation of protein catabolic process at postsynapse, modulating synaptic transmission;cellular response to nerve growth factor stimulus
• Cellular component: nucleus;cytoplasm;early endosome;cytosol;postsynaptic density;extrinsic component of plasma membrane;midbody;extrinsic component of endosome membrane;dendritic spine;glutamatergic synapse
• Molecular function: cysteine-type endopeptidase activity;thiol-dependent ubiquitin-specific protease activity;protein binding;SH3 domain binding;cadherin binding