ATXN3

ataxin 3, the group of MJD deubiquinating enzymes

Basic information

Region (hg38): 14:92044495-92106621

Previous symbols: [ "SCA3", "MJD" ]

Links

ENSG00000066427 ∙ NCBI:4287 ∙ OMIM:607047 ∙ HGNC:7106 ∙ Uniprot:P54252 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Machado-Joseph disease (Strong), mode of inheritance: AD
• Machado-Joseph disease (Definitive), mode of inheritance: AD
• Machado-Joseph disease type 1 (Supportive), mode of inheritance: AD
• Machado-Joseph disease type 2 (Supportive), mode of inheritance: AD
• Machado-Joseph disease type 3 (Supportive), mode of inheritance: AD
• Machado-Joseph disease (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia 3 (Machado-Joseph disease)	AD	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	Neurologic	5061839; 865531; 7874163; 7573040; 7496771; 7795637; 7633439; 7561932; 7655453; 8619527; 8640226; 9403486; 11176969; 15457499; 15747371; 20301375; 21555642; 21635785; 22023810

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATXN3 gene.

• Inborn genetic diseases (12 variants)
• not provided (11 variants)
• not specified (8 variants)
• Tip-toe gait (1 variants)
• Azorean disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATXN3 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				2	1	3
missense			12		1	13
nonsense						0
start loss						0
frameshift			1			1
inframe indel			4	1	5	10
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			1			1
Total	0	0	18	3	7

Variants in ATXN3

This is a list of pathogenic ClinVar variants found in the ATXN3 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-92064333-T-C		Inborn genetic diseases	Uncertain significance (Jun 28, 2022)
14-92064346-C-A		Inborn genetic diseases	Uncertain significance (Jun 27, 2022)
14-92070849-A-G			Likely benign (Dec 01, 2022)
14-92070979-C-T		Inborn genetic diseases	Uncertain significance (Jun 21, 2022)
14-92071009-C-CG		not specified • ATXN3-related disorder	Conflicting classifications of pathogenicity (Nov 04, 2019)
14-92071010-C-G		not specified • Azorean disease • ATXN3-related disorder	Benign (Oct 07, 2019)
14-92071009-C-CGCTGCT			Uncertain significance (Jan 01, 2023)
14-92071009-C-CCCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT			Likely benign (Dec 01, 2023)
14-92071010-C-GCTGCTGCTGCTGCTGCTG			Uncertain significance (Oct 03, 2019)
14-92071009-C-CGCTGCTGCTGCTGCTG			Uncertain significance (-)
14-92071010-C-CTG			Uncertain significance (-)
14-92071010-C-CCTG			Likely benign (Apr 01, 2023)
14-92071010-C-CCTGCTG		not specified	Benign (May 03, 2017)
14-92071010-C-CCTGCTGCTG			Uncertain significance (Nov 03, 2021)
14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTG			Benign (Nov 27, 2020)
14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG		not specified	Benign (May 05, 2015)
14-92071010-C-CTGCTGCTGCTGCTGCTG			Uncertain significance (-)
14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTG		ATXN3-related disorder	Benign (Jun 16, 2020)
14-92071010-C-CTGCTGCTGCTGCTGCTGCTG		not specified	Benign (-)
14-92071010-C-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG			Likely benign (-)
14-92071010-C-CCTGCTGCTGCTG		Azorean disease	Benign (Nov 16, 2018)
14-92071010-C-CCTGCTGCTGCTGCTG			Benign (Dec 01, 2023)
14-92071020-C-CTGCTGCTGCTGCTGT		ATXN3-related disorder	Benign (Oct 31, 2019)
14-92071034-G-GC		ATXN3-related disorder	Benign (Nov 25, 2019)
14-92071035-T-C		not specified • ATXN3-related disorder	Benign/Likely benign (Nov 21, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATXN3	protein_coding	protein_coding	ENST00000393287	11	48070

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.106	0.894	112988	727	12033	125748	0.0521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.35	136	188	0.723	0.00000928	2373
Missense in Polyphen		15	37.296	0.40219		519
Synonymous	1.21	52	64.4	0.808	0.00000321	625
Loss of Function	3.53	7	26.7	0.262	0.00000140	291

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.106	0.0981
Ashkenazi Jewish	0.0482	0.0432
East Asian	0.112	0.108
Finnish	0.0514	0.0445
European (Non-Finnish)	0.0437	0.0408
Middle Eastern	0.112	0.108
South Asian	0.0975	0.0922
Other	0.0518	0.0475

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:12297501, PubMed:17696782, PubMed:23625928, PubMed:28445460, PubMed:16118278). Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (PubMed:17696782). Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (By similarity). Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription (PubMed:12297501). Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (PubMed:28445460). {ECO:0000250|UniProtKB:Q9CVD2, ECO:0000269|PubMed:12297501, ECO:0000269|PubMed:16118278, ECO:0000269|PubMed:17696782, ECO:0000269|PubMed:23625928, ECO:0000269|PubMed:28445460}.
• Disease: DISEASE: Spinocerebellar ataxia 3 (SCA3) [MIM:109150]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA3 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. The molecular defect in SCA3 is the a CAG repeat expansion in ATX3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. {ECO:0000269|PubMed:7874163}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Protein processing in endoplasmic reticulum - Homo sapiens (human);Josephin domain DUBs;Post-translational protein modification;Metabolism of proteins;Deubiquitination (Consensus)

Recessive Scores

• pRec: 0.348

Intolerance Scores

• loftool: 0.895
• rvis_EVS: 0.28
• rvis_percentile_EVS: 71.27

Haploinsufficiency Scores

• pHI: 0.159
• hipred: Y
• hipred_score: 0.545
• ghis: 0.522

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.974

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atxn3
• Phenotype: homeostasis/metabolism 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: atxn3
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: microtubule cytoskeleton organization;nucleotide-excision repair;ubiquitin-dependent protein catabolic process;protein quality control for misfolded or incompletely synthesized proteins;chemical synaptic transmission;nervous system development;regulation of cell-substrate adhesion;protein deubiquitination;actin cytoskeleton organization;cellular response to heat;monoubiquitinated protein deubiquitination;exploration behavior;proteasome-mediated ubiquitin-dependent protein catabolic process;intermediate filament cytoskeleton organization;protein K63-linked deubiquitination;histone H3 deacetylation;protein K48-linked deubiquitination;cellular response to misfolded protein;positive regulation of ERAD pathway;protein localization to cytosolic proteasome complex involved in ERAD pathway
• Cellular component: nucleus;nucleoplasm;nucleolus;cytoplasm;mitochondrial matrix;endoplasmic reticulum membrane;cytosol;plasma membrane;nuclear matrix;mitochondrial membrane;nuclear inclusion body
• Molecular function: RNA polymerase II regulatory region DNA binding;histone deacetylase activity;thiol-dependent ubiquitin-specific protease activity;protein binding;ubiquitin protein ligase binding;thiol-dependent ubiquitinyl hydrolase activity;ATPase binding;Lys63-specific deubiquitinase activity;Lys48-specific deubiquitinase activity