TUBB4A

tubulin beta 4A class IVa, the group of Tubulins

Basic information

Region (hg38): 19:6494319-6502848

Previous symbols: [ "TUBB4", "DYT4" ]

Links

ENSG00000104833 ∙ NCBI:10382 ∙ OMIM:602662 ∙ HGNC:20774 ∙ Uniprot:P04350 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypomyelinating leukodystrophy 6 (Moderate), mode of inheritance: AD
• torsion dystonia 4 (Strong), mode of inheritance: AD
• torsion dystonia 4 (Supportive), mode of inheritance: AD
• hypomyelinating leukodystrophy 6 (Supportive), mode of inheritance: AD
• hypomyelinating leukodystrophy 6 (Definitive), mode of inheritance: AD
• torsion dystonia 4 (Strong), mode of inheritance: AD
• hypomyelinating leukodystrophy 6 (Strong), mode of inheritance: AD
• TUBB4A-related neurologic disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dystonia 4, torsion, autosomal dominant; Leukodystrophy, hypomyelinating, 6	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	3156966; 23582646; 23595291; 24013879; 24526230; 24742798; 24850488; 25085639

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TUBB4A gene.

• Hypomyelinating leukodystrophy 6 (10 variants)
• not provided (7 variants)
• 6 conditions (1 variants)
• Auditory neuropathy spectrum disorder (1 variants)
• Hypomyelinating leukodystrophy 6;Torsion dystonia 4 (1 variants)
• Torsion dystonia 4 (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TUBB4A 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			5	91	6	102
missense	11	25	67	4		107
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			1	5		6
non coding			8	13	22	43
Total	11	25	84	108	28

Variants in TUBB4A

This is a list of pathogenic ClinVar variants found in the TUBB4A region.

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

Position	Type	Phenotype	Significance	ClinVar
19-6494360-G-C		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Apr 27, 2017)
19-6494364-C-T		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Uncertain significance (Apr 28, 2017)
19-6494372-G-A		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Uncertain significance (Jan 13, 2018)
19-6494439-C-T		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Benign (Jan 12, 2018)
19-6494464-A-T		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Benign (Apr 27, 2017)
19-6494491-T-C		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Apr 27, 2017)
19-6494531-G-T		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Jan 13, 2018)
19-6494537-T-G		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Uncertain significance (Jan 13, 2018)
19-6494585-G-A		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Uncertain significance (Jan 12, 2018)
19-6494671-G-C		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Jan 12, 2018)
19-6494724-G-A		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Uncertain significance (Jan 12, 2018)
19-6494735-G-A		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Jan 13, 2018)
19-6494764-C-T		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Feb 26, 2021)
19-6494860-G-A		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Uncertain significance (Jan 13, 2018)
19-6494904-C-G		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Jun 19, 2018)
19-6495053-C-G		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Benign (Jun 26, 2018)
19-6495064-C-T		Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Benign (Jan 13, 2018)
19-6495068-G-C		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Jul 06, 2018)
19-6495078-C-T		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Uncertain significance (Jan 13, 2018)
19-6495095-G-C		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Apr 27, 2017)
19-6495111-C-T		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Likely benign (Apr 27, 2017)
19-6495128-G-C		Hypomyelinating leukodystrophy 6 • Torsion dystonia 4	Benign (Jan 13, 2018)
19-6495161-A-G		not specified • Torsion dystonia 4 • Hypomyelinating leukodystrophy 6	Benign (Jan 12, 2018)
19-6495168-G-A		Hypomyelinating leukodystrophy 6	Uncertain significance (Aug 15, 2022)
19-6495170-C-T		Hypomyelinating leukodystrophy 6	Conflicting classifications of pathogenicity (Oct 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TUBB4A	protein_coding	protein_coding	ENST00000264071	4	8530

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.109	0.885	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.26	93	301	0.309	0.0000234	2941
Missense in Polyphen		33	124.5	0.26505		1288
Synonymous	-1.48	159	137	1.16	0.0000125	877
Loss of Function	2.41	4	13.6	0.294	5.95e-7	148

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000616	0.0000615
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.000167	0.000163

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.
• Disease: DISEASE: Dystonia 4, torsion, autosomal dominant (DYT4) [MIM:128101]: A form of torsion dystonia, a disease defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. 'Torsion' refers to the twisting nature of body movements, often affecting the trunk. DYT4 is characterized by onset in the second to third decade of progressive laryngeal dysphonia followed by the involvement of other muscles, such as the neck or limbs. Some patients develop an ataxic gait. {ECO:0000269|PubMed:23424103}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukodystrophy, hypomyelinating, 6 (HLD) [MIM:612438]: A neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. {ECO:0000269|PubMed:23582646}. 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;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;Regulation of PLK1 Activity at G2/M Transition;Recruitment of mitotic centrosome proteins and complexes;Loss of Nlp from mitotic centrosomes;Loss of proteins required for interphase microtubule organization from the centrosome;Centrosome maturation;AURKA Activation by TPX2;G2/M Transition;Mitotic G2-G2/M phases;Protein folding;Recruitment of NuMA to mitotic centrosomes;Mitotic Prometaphase;M Phase;Cell Cycle;Prefoldin mediated transfer of substrate to CCT/TriC;Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding;Post-chaperonin tubulin folding pathway;Cell Cycle, Mitotic;Anchoring of the basal body to the plasma membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Intolerance Scores

• rvis_EVS: -0.76
• rvis_percentile_EVS: 13.33

Haploinsufficiency Scores

• pHI: 0.388
• hipred: Y
• hipred_score: 0.501
• ghis: 0.626

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.114

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tubb4a

Gene ontology

• Biological process: G2/M transition of mitotic cell cycle;microtubule cytoskeleton organization;mitotic cell cycle;microtubule-based process;regulation of G2/M transition of mitotic cell cycle;negative regulation of microtubule polymerization;ciliary basal body-plasma membrane docking
• Cellular component: nucleus;cytoplasm;cytosol;microtubule;axoneme;internode region of axon;neuronal cell body;myelin sheath;extracellular exosome
• Molecular function: GTPase activity;structural constituent of cytoskeleton;calcium ion binding;protein binding;GTP binding