USP9X

ubiquitin specific peptidase 9 X-linked, the group of Ubiquitin specific peptidases|Armadillo like helical domain containing

Basic information

Region (hg38): X:41085445-41236579

Links

ENSG00000124486 ∙ NCBI:8239 ∙ OMIM:300072 ∙ HGNC:12632 ∙ Uniprot:Q93008 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, X-linked 99 (Strong), mode of inheritance: XL
• intellectual disability, X-linked 99, syndromic, female-restricted (Strong), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability (Supportive), mode of inheritance: XL
• intellectual disability, X-linked 99, syndromic, female-restricted (Strong), mode of inheritance: XL
• intellectual disability, X-linked 99 (Strong), mode of inheritance: XL
• X-linked syndromic intellectual disability (Definitive), mode of inheritance: XL
• intellectual disability, X-linked 99, syndromic, female-restricted (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked 99; Intellectual developmental disorder, X-linked 99, syndromic, female restricted	XL	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic	19377476; 24607389; 26833328

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the USP9X gene.

• not_provided (765 variants)
• Inborn_genetic_diseases (102 variants)
• Intellectual_disability,_X-linked_99 (79 variants)
• Intellectual_disability,_X-linked_99,_syndromic,_female-restricted (72 variants)
• USP9X-related_disorder (42 variants)
• not_specified (17 variants)
• Intellectual_disability (9 variants)
• See_cases (4 variants)
• USP9X-related_neurodevelopmental_disorder (3 variants)
• Neurodevelopmental_disorder (2 variants)
• Global_developmental_delay (1 variants)
• Neurodevelopmental_delay (1 variants)
• Developmental_delay (1 variants)
• Hereditary_ataxia (1 variants)
• Severe_intellectual_deficiency (1 variants)
• Congenital_myopathy (1 variants)
• Hyperpigmentation_of_the_skin (1 variants)
• Intellectual_disability,_X-linked_101 (1 variants)
• USP9X-related_intellectual_developmental_disorder (1 variants)
• Neurodevelopmental_abnormality (1 variants)
• Developmental_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the USP9X gene is commonly pathogenic or not. These statistics are base on transcript: NM_001039591.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	14	125	26	166
missense	5	29	449	41	8	532
nonsense	26	6				32
start loss						0
frameshift	34	11	2			47
splice donor/acceptor (+/-2bp)	4	6	1			11
Total	69	53	466	166	34

Highest pathogenic variant AF is 0.00000273389

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
USP9X	protein_coding	protein_coding	ENST00000324545	44	150945

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	6.10e-15	125270	4	10	125284	0.0000559

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.41	378	927	0.408	0.0000697	17036
Missense in Polyphen		118	434.43	0.27162		8322
Synonymous	0.407	311	320	0.971	0.0000237	4760
Loss of Function	8.86	1	93.5	0.0107	0.00000746	1619

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000195	0.000173
Ashkenazi Jewish	0.000135	0.0000993
East Asian	0.00	0.00
Finnish	0.0000626	0.0000462
European (Non-Finnish)	0.0000986	0.0000705
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes 'Lys-48'-, 'Lys- 29'- and 'Lys-33'-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration (PubMed:16322459, PubMed:18254724, PubMed:19135894, PubMed:24607389). {ECO:0000269|PubMed:16322459, ECO:0000269|PubMed:18254724, ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:24607389, ECO:0000269|PubMed:25944111}.
• Pathway: Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Post-translational protein modification;Metabolism of proteins;RNA Polymerase II Transcription;Synthesis of active ubiquitin: roles of E1 and E2 enzymes;Peroxisomal protein import;Downregulation of SMAD2/3:SMAD4 transcriptional activity;Amyloid fiber formation;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;Ub-specific processing proteases;Deubiquitination;Protein ubiquitination;Signaling by TGF-beta Receptor Complex;Signaling by TGF-beta family members (Consensus)

Recessive Scores

• pRec: 0.103

Intolerance Scores

• rvis_EVS: -1.62
• rvis_percentile_EVS: 2.93

Haploinsufficiency Scores

• pHI: 0.581
• hipred: Y
• hipred_score: 0.647
• ghis: 0.642

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.702

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Usp9x
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; 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); normal 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); neoplasm; embryo phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;neuron migration;protein targeting to peroxisome;cell cycle;chromosome segregation;transforming growth factor beta receptor signaling pathway;female gamete generation;protein deubiquitination;BMP signaling pathway;regulation of circadian rhythm;cellular protein metabolic process;axon extension;protein stabilization;cell division;protein K48-linked deubiquitination;protein deubiquitination involved in ubiquitin-dependent protein catabolic process;positive regulation of DNA demethylation
• Cellular component: cytoplasm;cytosol;membrane;growth cone
• Molecular function: cysteine-type endopeptidase activity;thiol-dependent ubiquitin-specific protease activity;protein binding;cysteine-type peptidase activity;thiol-dependent ubiquitinyl hydrolase activity;co-SMAD binding;ubiquitinyl hydrolase activity;Lys48-specific deubiquitinase activity