BUB1B
protein-codingBUB1 mitotic checkpoint serine/threonine kinase B
Gene summary
This gene encodes a kinase involved in spindle checkpoint function. The protein has been localized to the kinetochore and plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Impaired spindle checkpoint function has been found in many forms of cancer. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~60.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0000141
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009759
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0005387
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0005212
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009759
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009759
Submitter: ClinGen
BUBR1 protein encoded by BUB1B gene is an important protein in the spindle assembly checkpoint. Constitutional homozygotes of hypomorphic mutations or compound heterozygote of a null mutation and a missense/hypomorphic mutation in the BUB1B gene cause the rare human disorder mosaic variegated aneuploidy (MVA) syndrome type I (MIM 257300). Hanks S et al., (2004) identified 6 individuals from 5 unrelated families with typical phenotypes of MVA carry biallelic BUB1B mutations. Rio Frio T et al. (2010) identified a male of 34 yr-old from a consanguineous family with MVA phenotype and many types of cancers homozygous for BUB1B 2386-11A>G mutation. Ochiai H et al., (2004) found a Japanese infant with MVA homozygous for mutation ss802470619,NC_000015.10:g.40117088G>A (GRCh38), which is the second allele to the seven individuals who had one allele previously identified (Matsuura S, et al. (2006)). This mutation is a hypomorphic mutation that down regulate the expression of BUB1B gene. Using human HeLa cells Bohers et al. (2008) showed the levels of PCS (premature chromatid separation) and aneuploidy were correlated to the decrease of BUB1B expression. BubR1−/− embryos present mosaicism with a significant percentage of aneuploid cells and premature chromatic separation, growth retardation and marked developmental abnormalities. Progressive apoptosis and reduced cell proliferation finally lead to severe morphological malformation and embryonic death (Schmid M et al., 2014.). More evidence is available in literatures, but the maximum score from genetic evidence and experimental evidences has been reached. In summary, BUB1B gene is definitively associated with mosaic variegated aneuploidy syndrome 1. Variants in this gene have been independently and replicably identified in many individuals with MVA.
Inheritance Pattern: AR
Disease ID:MONDO:0009759
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009759
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic; Obstetric; Oncologic; Ophthalmologic
Intervention: Obstetric; Oncologic
Rationale: Mosaic variegated aneuploidy syndrome is frequently but not always clinically recognizable, and there is a high risk of malignancy, for which surveillance and early treatment may be beneficial; Premature chromatid separation has been described as potentially affecting fertility, and reproductive counseling as well as preconception planning may be beneficial
Comments: The condition can involve a number of congenital anomalies
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BUB1B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001211.6. 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 | 7 | 613 | 4 | 624 | ||
| missense | 2 | 1482 | 57 | 3 | 1544 | |
| nonsense | 27 | 8 | 3 | 38 | ||
| start loss | 1 | 1 | ||||
| frameshift | 28 | 11 | 5 | 44 | ||
| splice donor/acceptor (+/-2bp) | 1 | 10 | 4 | 15 | ||
| Total | 56 | 31 | 1502 | 670 | 7 | 2266 |
Highest pathogenic variant AF is 0.00007434852
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001202.5 | 23 | MANE Select | |
| Ensembl | ENSP00000287598.7 | 23 | MANE Select | |
| Ensembl | ENSP00000398470.3 | 23 | Standard | |
| Ensembl | ENSP00000398470.3 | 23 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
- Cell Cycle
- Regulation of sister chromatid separation at the metaphase-anaphase transition
- Signal Transduction
Biological Process
- mitotic cell cycle
- protein phosphorylation
- apoptotic process
- metaphase/anaphase transition of mitotic cell cycle
- mitotic cell cycle checkpoint
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- protein binding
- ATP binding
Cellular Component
- kinetochore
- condensed chromosome kinetochore
- condensed nuclear chromosome kinetochore
- condensed chromosome outer kinetochore
- anaphase-promoting complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000287598
- Coding exons
- 23
- Length
- 60114
- Individuals with no LoFs
- 125673
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 75
- Defined
- 125748
- p
- 0.000298
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.893 | 482 | 540 | 0.892 | 0.0000277 | 6924 |
| Missense (PolyPhen) | 122 | 154.84 | 0.78789 | 1996 | ||
| Synonymous | -0.0608 | 188 | 187 | 1.01 | 0.00000937 | 1938 |
| Loss of Function | 4.31 | 27 | 64.2 | 0.420 | 0.00000363 | 723 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00032 | 0.00032 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphase-promoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE. Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression. {ECO:0000269|PubMed:10477750, ECO:0000269|PubMed:11702782, ECO:0000269|PubMed:14706340, ECO:0000269|PubMed:15020684, ECO:0000269|PubMed:19411850, ECO:0000269|PubMed:19503101}.;
- Disease
- DISEASE: Note=Defects in BUB1B are associated with tumor formation.; DISEASE: Premature chromatid separation trait (PCS) [MIM:176430]: Consists of separate and splayed chromatids with discernible centromeres and involves all or most chromosomes of a metaphase. It is found in up to 2% of metaphases in cultured lymphocytes from approximately 40% of normal individuals. When PCS is present in 5% or more of cells, it is known as the heterozygous PCS trait and has no obvious phenotypic effect, although some have reported decreased fertility. Inheritance is autosomal dominant. {ECO:0000269|PubMed:16411201}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mosaic variegated aneuploidy syndrome 1 (MVA1) [MIM:257300]: A severe developmental disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor and leukemia reported in several cases. {ECO:0000269|PubMed:15475955}. Note=The disease is caused by mutations affecting the gene represented in this entry. MVA1 is caused by biallelic mutations in the BUB1B gene.;
Recessive Scores
- pRec
- 0.263
Intolerance Scores
- LoFtool
- 0.865
- RVIS EVS
- -0.06
- RVIS percentile EVS
- 48.87
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.856
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |