BUB1B

BUB1 mitotic checkpoint serine/threonine kinase B

Basic information

Region (hg38): 15:40161023-40221123

Links

ENSG00000156970 ∙ NCBI:701 ∙ OMIM:602860 ∙ HGNC:1149 ∙ Uniprot:O60566 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mosaic variegated aneuploidy syndrome 1 (Definitive), mode of inheritance: AR
• rhabdomyosarcoma (Moderate), mode of inheritance: AR
• mosaic variegated aneuploidy syndrome 1 (Strong), mode of inheritance: AR
• mosaic variegated aneuploidy syndrome (Supportive), mode of inheritance: AD
• mosaic variegated aneuploidy syndrome 1 (Strong), mode of inheritance: AR
• mosaic variegated aneuploidy syndrome 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mosaic variegated aneuploidy syndrome 1; Premature chromatid separation trait	AD/AR	Obstetric; Oncologic	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	Musculoskeletal; Neurologic; Obstetric; Oncologic; Ophthalmologic	2935477; 3780318; 8225320; 9677059; 10429359; 9916837; 11169558; 11746029; 15475955; 15098246; 16411201; 21190457
The condition can involve a number of congenital anomalies

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BUB1B gene.

• Mosaic variegated aneuploidy syndrome 1 (44 variants)
• not provided (2 variants)
• Premature chromatid separation trait (2 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 BUB1B 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			4	409	7	420
missense		1	928	20	4	953
nonsense	25	4	2			31
start loss			1			1
frameshift	21	4	1			26
inframe indel			6			6
splice donor/acceptor (+/-2bp)		6	2			8
splice region			30	46	1	77
non coding			5	101	46	152
Total	46	15	949	530	57

Highest pathogenic variant AF is 0.0000197

Variants in BUB1B

This is a list of pathogenic ClinVar variants found in the BUB1B region.

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

Position	Type	Phenotype	Significance	ClinVar
15-40161106-A-G			Benign (Jan 10, 2019)
15-40161179-A-G			Likely benign (Feb 24, 2019)
15-40161221-A-AT		Mosaic variegated aneuploidy syndrome 1	Uncertain significance (Aug 31, 2020)
15-40161226-G-A		Inborn genetic diseases • Mosaic variegated aneuploidy syndrome 1	Likely benign (Jan 04, 2024)
15-40161226-G-C		Inborn genetic diseases	Likely benign (Nov 09, 2020)
15-40161227-G-A		Inborn genetic diseases	Uncertain significance (Feb 06, 2022)
15-40161228-C-T		Inborn genetic diseases	Uncertain significance (Oct 16, 2023)
15-40161229-G-A		Inborn genetic diseases	Likely benign (Apr 19, 2022)
15-40161229-G-T		not specified • Mosaic variegated aneuploidy syndrome 1 • Colorectal cancer	Benign (Feb 01, 2024)
15-40161230-G-A		not specified • Mosaic variegated aneuploidy syndrome 1 • Inborn genetic diseases • BUB1B-related disorder	Likely benign (Jan 25, 2024)
15-40161235-G-A		Mosaic variegated aneuploidy syndrome 1 • Inborn genetic diseases	Likely benign (Sep 08, 2023)
15-40161238-G-A		Inborn genetic diseases	Likely benign (Jul 15, 2022)
15-40161239-G-A		Mosaic variegated aneuploidy syndrome 1 • Inborn genetic diseases	Uncertain significance (Apr 07, 2024)
15-40161241-A-C		Mosaic variegated aneuploidy syndrome 1 • Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
15-40161241-A-G		Inborn genetic diseases	Likely benign (Jan 16, 2021)
15-40161242-G-C		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)
15-40161242-G-T		Mosaic variegated aneuploidy syndrome 1	Uncertain significance (Oct 01, 2022)
15-40161243-G-C		Mosaic variegated aneuploidy syndrome 1 • Inborn genetic diseases	Uncertain significance (Oct 29, 2022)
15-40161243-G-T		Inborn genetic diseases	Uncertain significance (May 05, 2024)
15-40161244-G-A		Inborn genetic diseases	Likely benign (Oct 29, 2022)
15-40161245-G-A		Inborn genetic diseases	Uncertain significance (Jan 07, 2024)
15-40161246-G-A		Mosaic variegated aneuploidy syndrome 1	Uncertain significance (Feb 22, 2023)
15-40161246-G-C		Mosaic variegated aneuploidy syndrome 1 • Inborn genetic diseases	Uncertain significance (Feb 03, 2023)
15-40161246-G-T		Mosaic variegated aneuploidy syndrome 1	Uncertain significance (Mar 29, 2021)
15-40161247-T-A		Inborn genetic diseases	Likely benign (Jun 07, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BUB1B	protein_coding	protein_coding	ENST00000287598	23	60114

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.00e-10	1.00	125673	0	75	125748	0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.893	482	540	0.892	0.0000277	6924
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000724	0.000724
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.000381	0.000381
Finnish	0.00	0.00
European (Non-Finnish)	0.000317	0.000316
Middle Eastern	0.000381	0.000381
South Asian	0.000392	0.000392
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal;Amplification of signal from the kinetochores;Inactivation of APC/C via direct inhibition of the APC/C complex;Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components;Mitotic Spindle Checkpoint;Cell Cycle Checkpoints;RHO GTPases Activate Formins;RHO GTPase Effectors;Signaling by Rho GTPases;Mitotic Prometaphase;Separation of Sister Chromatids;Mitotic Anaphase;Mitotic Metaphase and Anaphase;M Phase;Regulation of APC/C activators between G1/S and early anaphase;Cdc20:Phospho-APC/C mediated degradation of Cyclin A;APC-Cdc20 mediated degradation of Nek2A;APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint;APC/C:Cdc20 mediated degradation of mitotic proteins;Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins;APC/C-mediated degradation of cell cycle proteins;Regulation of mitotic cell cycle;Cell Cycle;Resolution of Sister Chromatid Cohesion;Cell Cycle, Mitotic;PLK1 signaling events (Consensus)

Recessive Scores

• pRec: 0.263

Intolerance Scores

• loftool: 0.865
• rvis_EVS: -0.06
• rvis_percentile_EVS: 48.87

Haploinsufficiency Scores

• pHI: 0.921
• hipred: Y
• hipred_score: 0.580
• ghis: 0.631

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.856

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Bub1b
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; skeleton phenotype; embryo phenotype; respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; neoplasm; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype

Gene ontology

• Biological process: mitotic cell cycle;protein phosphorylation;apoptotic process;metaphase/anaphase transition of mitotic cell cycle;mitotic cell cycle checkpoint;mitotic spindle assembly checkpoint;cell population proliferation;anaphase-promoting complex-dependent catabolic process;cell division;meiotic sister chromatid cohesion, centromeric;protein localization to chromosome, centromeric region;regulation of mitotic cell cycle phase transition
• Cellular component: kinetochore;condensed chromosome kinetochore;condensed nuclear chromosome kinetochore;condensed chromosome outer kinetochore;anaphase-promoting complex;cytoplasm;microtubule organizing center;spindle;cytosol;perinuclear region of cytoplasm
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;protein binding;ATP binding