TUBB3

tubulin beta 3 class III, the group of Tubulins

Basic information

Region (hg38): 16:89921391-89938761

Previous symbols: [ "FEOM3" ]

Links

ENSG00000258947 ∙ NCBI:10381 ∙ OMIM:602661 ∙ HGNC:20772 ∙ Uniprot:Q13509 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (Strong), mode of inheritance: AD
• complex cortical dysplasia with other brain malformations 1 (Strong), mode of inheritance: AD
• fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (Strong), mode of inheritance: AD
• congenital fibrosis of extraocular muscles (Supportive), mode of inheritance: AD
• complex cortical dysplasia with other brain malformations 1 (Supportive), mode of inheritance: AD
• tubulinopathy-associated dysgyria (Supportive), mode of inheritance: AD
• complex cortical dysplasia with other brain malformations 1 (Strong), mode of inheritance: AD
• complex cortical dysplasia with other brain malformations 1 (Strong), mode of inheritance: AD
• fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cortical dysplasia, complex, with other brain malformations 1; Fibrosis of extraocular muscles, congenital, 3A	AD/AR	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	Musculoskeletal; Neurologic	7724178; 10393037; 12073023; 20829227; 20074521

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TUBB3 gene.

• not provided (214 variants)
• not specified (33 variants)
• Complex cortical dysplasia with other brain malformations 1 (32 variants)
• Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (10 variants)
• Inborn genetic diseases (9 variants)
• TUBB3-related condition (4 variants)
• Complex cortical dysplasia with other brain malformations 1;Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (3 variants)
• See cases (2 variants)
• TUBB3-related tubulinopathy (2 variants)
• Abnormal cerebral morphology (1 variants)
• X-linked hydrocephalus syndrome (1 variants)
• TUBB3-Releated Disorders (1 variants)
• Developmental disorder (1 variants)
• Neurodevelopmental disorder (1 variants)
• Arrhythmogenic right ventricular dysplasia 8 (1 variants)
• TUBB3-related disorders (1 variants)
• Spastic ataxia (1 variants)
• TUBB3-Related Disorder (1 variants)
• Martsolf syndrome 1 (1 variants)
• Congenital fibrosis of extraocular muscles type 1;Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement;Congenital Fibrosis of the Extraocular Muscles 1B;Complex cortical dysplasia with other brain malformations 1 (1 variants)
• Brain malformation;Congenital fibrosis of extraocular muscles (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TUBB3 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			4	55	6	65
missense	12	24	87	3		126
nonsense			4			4
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	1	2	5
non coding				11	17	28
Total	12	24	96	69	23

Variants in TUBB3

This is a list of pathogenic ClinVar variants found in the TUBB3 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-89923044-G-A			Benign (Jun 26, 2018)
16-89923113-T-A			Likely benign (Jun 26, 2018)
16-89923273-C-T			Likely benign (Mar 16, 2019)
16-89923372-G-T			Likely benign (May 23, 2018)
16-89923406-G-A		Complex cortical dysplasia with other brain malformations 1	Conflicting classifications of pathogenicity (Aug 09, 2023)
16-89923406-G-T			Uncertain significance (Oct 17, 2023)
16-89923410-G-C			Uncertain significance (Jan 17, 2020)
16-89923432-C-A			Uncertain significance (Mar 08, 2023)
16-89923434-G-C		X-linked hydrocephalus syndrome	Uncertain significance (Sep 30, 2021)
16-89923447-A-T			Uncertain significance (Aug 06, 2019)
16-89923450-G-C			Uncertain significance (Dec 21, 2023)
16-89923451-G-T			Uncertain significance (Sep 28, 2022)
16-89923475-C-T			Likely benign (Oct 04, 2023)
16-89932240-T-G			Benign (Jun 26, 2018)
16-89932336-C-G			Benign (Jun 26, 2018)
16-89932386-G-A			Benign (Jun 14, 2018)
16-89932522-C-T		not specified	Benign (Jun 26, 2018)
16-89932544-A-AC			Benign (Feb 14, 2020)
16-89932549-C-T		not specified	Benign (Jun 26, 2018)
16-89932550-C-G			Benign (Jul 21, 2018)
16-89932551-C-T			Likely benign (Oct 17, 2023)
16-89932551-CT-C		not specified	Likely benign (Apr 06, 2023)
16-89932552-T-C			Benign (Apr 06, 2023)
16-89932554-T-C			Likely benign (Jun 15, 2022)
16-89932568-C-A			Uncertain significance (Sep 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TUBB3	protein_coding	protein_coding	ENST00000315491	4	17370

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.968	0.0324	125709	0	3	125712	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.58	77	300	0.256	0.0000234	2991
Missense in Polyphen		14	123.86	0.11303		1323
Synonymous	-2.22	172	139	1.24	0.0000130	879
Loss of Function	3.36	1	15.0	0.0665	7.29e-7	163

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000616	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. TUBB3 plays a critical role in proper axon guidance and mantainance. {ECO:0000269|PubMed:20074521}.
• Disease: DISEASE: Fibrosis of extraocular muscles, congenital, 3A (CFEOM3A) [MIM:600638]: A congenital ocular motility disorder marked by restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. It is clinically characterized by anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. Congenital fibrosis of extraocular muscles type 3 presents as a non-progressive, autosomal dominant disorder with variable expression. Patients may be bilaterally or unilaterally affected, and their oculo-motility defects range from complete ophthalmoplegia (with the eyes fixed in a hypo- and exotropic position), to mild asymptomatic restrictions of ocular movement. Ptosis, refractive error, amblyopia, and compensatory head positions are associated with the more severe forms of the disorder. In some cases, the ocular phenotype is accompanied by additional features including developmental delay, corpus callosum agenesis, basal ganglia dysmorphism, facial weakness, polyneuropathy. {ECO:0000269|PubMed:20074521}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cortical dysplasia, complex, with other brain malformations 1 (CDCBM1) [MIM:614039]: A disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved. {ECO:0000269|PubMed:20829227}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Phagosome - Homo sapiens (human);Gap junction - Homo sapiens (human);Pathogenic Escherichia coli infection - Homo sapiens (human);Pathogenic Escherichia coli infection;Parkin-Ubiquitin Proteasomal System pathway;Exercise-induced Circadian Regulation;Post-translational protein modification;Metabolism of proteins;Chaperonin-mediated protein folding;Formation of tubulin folding intermediates by CCT/TriC;Carboxyterminal post-translational modifications of tubulin;Protein folding;Prefoldin mediated transfer of substrate to CCT/TriC;Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding;Post-chaperonin tubulin folding pathway (Consensus)

Recessive Scores

• pRec: 0.701

Intolerance Scores

• loftool: 0.244
• rvis_EVS: -0.76
• rvis_percentile_EVS: 13.33

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.626
• ghis: 0.589

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.927

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tubb3
• Phenotype: cellular 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); respiratory system 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: microtubule cytoskeleton organization;mitotic cell cycle;microtubule-based process;axon guidance;neuron differentiation
• Cellular component: nucleus;cytoplasm;microtubule;axon;dendrite;extracellular exosome
• Molecular function: GTPase activity;structural constituent of cytoskeleton;protein binding;GTP binding