TUBB4A

protein-coding

tubulin beta 4A class IVa, the group of Tubulins

Gene summary

This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]

Previous symbols:

TUBB4
DYT4

MANE transcript

NM_006087.4

Inheritance

ClinVar variants

P:58U:138B:124

Top phenotype

Dystonia 4, torsion, autosomal dominant; Leukodystrophy, hypomyelinating, 6

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr19:6,494,319-6,502,848

External References & Databases

Ensembl (ENSG00000104833)

Transcript & Mutation Effects

hg38 • Region Span ~8.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

torsion dystonia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007493

Submitter: Genomics England PanelApp

leukodystrophy, hypomyelinating, 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: Illumina

torsion dystonia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007493

Submitter: PanelApp Australia

TUBB4A-related neurologic disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0800470

Submitter: Ambry Genetics

leukodystrophy, hypomyelinating, 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: Genomics England PanelApp

leukodystrophy, hypomyelinating, 6SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: Orphanet

leukodystrophy, hypomyelinating, 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: G2P

torsion dystonia 4SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007493

Submitter: Orphanet

torsion dystonia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007493

Submitter: Labcorp Genetics (formerly Invitae)

TUBB4A-related neurologic disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800470

Submitter: ClinGen

The association of TUBB4A variants with autosomal dominant neurological disease first occurred in 2013 with whispering dystonia type 4 (Hersheson et al., PMID: 23424103 and Lohmann et al., PMID: 23595291) and hypomyelination with atrophy of the basal ganglia and cerebellum (Simons et al., PMID: 23582646). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, and found that the spectrum of phenotypic variability could exist between the described disease entities. Therefore, the prior disease entities have been lumped into one disease entity, TUBB4A Related Neurologic Disorder (MONDO: 0800470). Clinical characteristics include a variable age of onset with a spectrum of physical and radiographical findings. The TUBB4A gene encodes a protein that is a member of the highly conserved β-tubulin protein family that forms heterodimers with α-tubulins and then in turn forms copolymers that assemble into microtubules, an essential component of the cytoskeleton and is primarily expressed in the nervous system. Eleven missense variants reported in fifteen probands across five publications (PMIDs: 25085639, 32943487, 23582646, and 33597727) including one with linkage analysis (PMID: 23595291) are included in this curation. The mechanism of pathogenicity is gain-of-function. Gene-disease relationship is supported by cellular-based expression studies (PMID: 35668344) and animal models including a mouse model (PMID: 32463361). More evidence exists in the literature, but the maximum required score for genetic evidence (12 pts.) has been reached. In summary, definitive evidence supports the relationship between TUBB4A and autosomal dominant TUBB4A Related Neurologic Disorder, with rigorous and reproducible evidence in research and clinical diagnostic settings. This gene-disease curation based on ClinGen criteria was approved by the Leukodystrophy and Leukoencephalopathy GCEP via email communications on March 6, 2024 (SOP Version 10).

leukodystrophy, hypomyelinating, 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Dystonia 4, torsion, autosomal dominant; Leukodystrophy, hypomyelinating, 6AD

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 3156966; 23582646; 23595291; 24013879; 24526230; 24742798; 24850488; 25085639

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBB4A variants in ClinVar

24 Conditions Cataloged

Leukodystrophy, hypomyelinating, 6Total: 240

not providedTotal: 133

not specifiedTotal: 57

Torsion dystonia 4Total: 30

TUBB4A-related disorderTotal: 30

Inborn genetic diseasesTotal: 20

Cerebral palsyTotal: 2

Global developmental delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006087.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	118 clinvar	2 clinvar	125
missense	8 clinvar	50 clinvar	128 clinvar	4 clinvar		190
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	8	50	138	122	2	320

Highest pathogenic variant AF is 0.0000013681575

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006087.4	RefSeq	NP_006078.2	4	MANE Select
ENST00000264071.7	Ensembl	ENSP00000264071.1	4	MANE Select
NM_001289123.2	RefSeq	NP_001276052.1	5	Standard
NM_001289127.2	RefSeq	NP_001276056.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

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

Molecular Function

GTPase activity
structural constituent of cytoskeleton
calcium ion binding
protein binding
GTP binding

Cellular Component

nucleus
cytoplasm
cytosol
microtubule
axoneme

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264071
Coding exons: 4
Length: 8530
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.26	93	301	0.309	0.0000234	2941
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

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.;

Intolerance Scores

RVIS EVS: -0.76
RVIS percentile EVS: 13.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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