TUBG1
protein-codingtubulin gamma 1, the group of Tubulins
Gene summary
This gene encodes a member of the tubulin superfamily. The encoded protein localizes to the centrosome where it binds to microtubules as part of a complex referred to as the gamma-tubulin ring complex. The protein mediates microtubule nucleation and is required for microtubule formation and progression of the cell cycle. A pseudogene of this gene is found on chromosome 7. [provided by RefSeq, Jan 2009]
- TUBG
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014171
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014171
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014171
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014171
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018838
Submitter: ClinGen
*TUBG1* gene encodes gamma-tubulin that forms the gamma-tubulin ring complex to serve as a scaffold for formation of microtubules (PMIDs: 30016746, 21993292). Pathogenic variants in TUBG1 related to malformation of cortical development was first reported in 2013 in relation to autosomal dominant lissencephaly or pachygyria with microcephaly or dysgenesis of corpus callosum (PMID: 23603762). Since then at least ten missense variants, including one recurrent variant, have been reported in 15 individuals in five publications (PMIDs: 23603762, 29706637, 31151415, 33728335, 33453472) with latest one from 2021. In absence of truncating variants, the mechanism of disease is dominant negative. The gene-disease relationship is also supported by experimental evidence (PMIDs: 21993292, 23603762, 31086189). In formation of microtubules, *TUBG1* interacts with *TUBA1A* and *TUBB2A* that are associated with complex brain malformation including lissencephaly. Additional mice models have shown association of *TUBG1* to cortical migration abnormalities that underlies pathophysiology of lissencephaly. As experiment evidence under model and rescue category exceeded the maximum of four points, variant specific experimental evidence from mouse model (PMID: 31086189) were used to provide additional support for functional evidence under genetic evidence. In summary, *TUBG1* is definitely associated with autosomal dominant lissencephaly, supported by clinical and experimental evidence demonstrated over time. This classification has been approved by the Brain Malformations Gene Curation Expert Panel on April 26, 2022 (SOP version 8).
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TUBG1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001070.5. 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 | 4 | 58 | 4 | 66 | ||
| missense | 2 | 13 | 61 | 2 | 78 | |
| nonsense | 3 | 1 | 4 | |||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 6 | |||
| Total | 2 | 14 | 77 | 61 | 4 | 158 |
Highest pathogenic variant AF is 6.8456484e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001061.2 | 11 | MANE Select | |
| Ensembl | ENSP00000251413.2 | 11 | MANE Select | |
| Ensembl | ENSP00000465582.1 | 5 | Standard | |
| Ensembl | ENSP00000464867.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tubg1 | Danio rerio | Structure: hepatocyte Quality: increased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Human papillomavirus infection - Homo sapiens (human)
- 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
Biological Process
- mitotic sister chromatid segregation
- G2/M transition of mitotic cell cycle
- meiotic spindle organization
- microtubule cytoskeleton organization
- mitotic cell cycle
Molecular Function
- GTPase activity
- structural constituent of cytoskeleton
- protein binding
- GTP binding
- identical protein binding
Cellular Component
- pericentriolar material
- condensed nuclear chromosome
- gamma-tubulin complex
- nucleus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000251413
- Coding exons
- 11
- Length
- 5559
- Individuals with no LoFs
- 125721
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 27
- Defined
- 125748
- p
- 0.000107
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.16 | 82 | 276 | 0.297 | 0.0000168 | 2966 |
| Missense (PolyPhen) | 23 | 107.15 | 0.21465 | 1234 | ||
| Synonymous | 0.0702 | 110 | 111 | 0.992 | 0.00000666 | 868 |
| Loss of Function | 3.27 | 6 | 22.9 | 0.262 | 0.00000107 | 255 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00090 | 0.00089 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tubulin is the major constituent of microtubules. The gamma chain is found at microtubule organizing centers (MTOC) such as the spindle poles or the centrosome. Pericentriolar matrix component that regulates alpha/beta chain minus-end nucleation, centrosome duplication and spindle formation.;
- Disease
- DISEASE: Cortical dysplasia, complex, with other brain malformations 4 (CDCBM4) [MIM:615412]: A disorder of aberrant neuronal migration and disturbed axonal guidance. Clinical features include early-onset seizures, microcephaly, spastic tetraplegia, and various malformations of cortical development, such as agyria, posterior or frontal pachygyria, thick cortex, and subcortical band heterotopia and thin corpus callosum in some patients. {ECO:0000269|PubMed:23603762}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.493
Intolerance Scores
- LoFtool
- 0.379
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.64
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.644
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |