BUB1B

Gene Facts

• HGNC Symbol: BUB1B (HGNC:1149)
• HGNC Name: BUB1 mitotic checkpoint serine/threonine kinase B
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: BUBR1, MAD3L, Bub1A, SSK1
• %HI: 14.21
• pLI: 0
• LOEUF: 0.71
• Cytoband: 15q15.1
• Genomic Coordinates:

  GRCh37/hg19:	chr15:40453270-40513324
  GRCh38/hg38:	chr15:40161069-40221123

• MANE Select Transcript: NM_001211.6 ENST00000287598.11
• 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 kinetoch... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-20462
• ClinGen Curation ID: CCID:006768
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Gene Associated with Autosomal Recessive Phenotype (30)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: No
• Last Evaluated: 02/02/2022

Haploinsufficiency (HI) Score Details

• HI Score: 30
• HI Evidence Strength: Gene Associated with Autosomal Recessive Phenotype

HI Disease

• Mosaic Variegated Aneuploidy Syndrome 1, Premature Chromatid Separation Trait

HI Evidence

• PUBMED: 15475955
  Hanks et al. (2004) reported five families with Mosaic Variegated Aneuploidy (MVA). Bi-allelic variants were identified in 4 families (one missense and one nonsense or the canonical "-1" splicing site variant). In the fifth family, only one missense variant was detected (maternally inherited), however, RT-PCR analysis showed no transcripts from the paternal allele indicating a bi-allelic loss of function of the BUB1B gene in this family. This finding is consistent with an autosomal recessive inheritance pattern of MVA.
• PUBMED: 16411201
  Matsuura et al (2006) reported 7 families with Premature Chromatid Separation (PCS)/Mosaic Variegated Aneuploidy (MVA). Probands in five families were directly tested. The genotype of the other two families were deduced via family member testing. Heterozygous nonsense or frameshift variants were detected. While no second alleles were identified in these families via an extensive sequencing (5-kb up- and down-stream of the gene), it was found that 6G3 haplotype is associated with a hypomorphic allele. In another study (Ochiai et al. 2014, PMID:28611924), the hypomorphic allele was determined to be NC_000015.10: g.40117088G>A (rs576524605). Bi-allelic introduction of this hypomorphic variants (rs576524605) into human cells showed an reduction of the BUB1B transcripts and an increased PCS frequency and MVA. These findings are consistent with an autosomal recessive pattern for BUB1B mutations.
• PUBMED: 28611924
  Kato et al. (2017) reported a prenatal diagnosis of Premature Chromatid Separation (PCS)/Mosaic Variegated Aneuploidy (MVA). The fetus was found to have microcephaly by ultrasound and to have PCS/MVA on amniotic fluid specimen. Genetic analysis showed a heterozygous rs576524605 allele and an insertion of the Alu-element right before the "AG" canonical splicing site of intron 8.
• PUBMED: 26658419
  Roberts et al. (2016) carried out WES for 638 patients with familial pancreatic cancer, heterozygous inactivation variants were detected in 3 patients. A marginal enrichment of the deleterious variants in the patient group was observed comparing to Bipolar Case-Control Study (BCCS). However, The effect of heterozygous BUB1B on cancer predisposition seems inconsistent from different studies.
• PUBMED: 27239782
  Hahn et al. (2016) sequenced 191 individuals with early onset (<50 years) colorectal cancer, and two heterozygous variants (p.Glu390del, p.Cys945Tyr) were detected. However, no difference in protein expression and localization were observed.

• HI Evidence Comments: The classical clinical phenotype of Mosaic Variegated Aneuploidy (MVA) / Premature Chromatic Separation (PCS) related to BUB1B deficiency are consistent with autosomal recessive inheritance. While some studies demonstrated an enrichment of heterozygous loss-of-function variants in cancer patient group (familial pancreatic cancer, early onset colorectal cancer) comparing to controls, this finding has not been confirmed by other clinical or laboratory studies. Additional Evidence: PMID:18932004 Bohers (2008) demonstrated that the PCS level correlates with the level of residual BUBR1 protein in a cellular model. While PCS is observed in cells with reduced BRBR1 protein, aneuploidy only observed in cells with BUBR1 level below 50%. PMID:31738183) In a mouse model, Sieben et al. (2020) noticed that mice carrying mono-allelic BubR1 mutations were prone to MVA-related pathologies later in life.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity