BUB1

protein-coding

BUB1 mitotic checkpoint serine/threonine kinase

Gene summary

This gene encodes a serine/threonine-protein kinase that play a central role in mitosis. The encoded protein functions in part by phosphorylating members of the mitotic checkpoint complex and activating the spindle checkpoint. This protein also plays a role in inhibiting the activation of the anaphase promoting complex/cyclosome. This protein may also function in the DNA damage response. Mutations in this gene have been associated with aneuploidy and several forms of cancer. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Previous symbols:

BUB1L

MANE transcript

NM_004336.5

Inheritance

AD, AR

ClinVar variants

P:6U:961B:490

Top phenotype

Microcephaly 30, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr2:110,637,528-110,678,063

External References & Databases

Ensembl (ENSG00000169679)

Transcript & Mutation Effects

hg38 • Region Span ~40.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

colorectal cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005575

Submitter: ClinGen

BUB1 is a mitotic serine-threonine protein kinase that functions with a complex of proteins to support proper chromosomal segregation and kinetochore binding. Loss of function variants in *BUB1* have been implicated in chromosomal segregation errors and aneuploidy. Biallelic *BUB1* mutations are associated with primary microcephaly-30 (MCPH30). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability; therefore the autosomal recessive condition has been split and this curation solely focuses on autosomal dominant colorectal cancer. Germline variants in *BUB1* were first reported in humans with colorectal cancer as early as 2013 (de Voer, et al., PMID: 23747338). At least 5 variants (truncating, missense, and splicing variants) identified in 5 individuals with colon cancer from 2 publications were included in this curation (2.7 points, PMID: 23747338, 29448935). These individuals were noted to have polyposis, mosaic aneuploidy, and/or mild dysmorphic features. However, a case-control study (PMID:27713038) found no evidence supporting *BUB1* and hereditary colorectal cancer (scored as contradictory evidence). Experimental evidence was included in this curation (1 point, PMIDs: 9521327, 11283619). Co-immunoprecipitation assay demonstrated that BUB1 interacts with APC. Colorectal cancer cell lines with *BUB1* mutations showed chromosomal instability. In summary, there is limited evidence to support this gene-disease relationship of *BUB1* and autosomal dominant colorectal cancer. This curation was approved by the ClinGen Hereditary Cancer GCEP on 6/23/2023 (SOP Version 9). Summary of Genetic Evidence: 2.7 points; Experimental Evidence: 1 point; Total: 3.7 points.

microcephaly 30, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859342

Submitter: PanelApp Australia

microcephaly 30, primary, autosomal recessiveLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0859342

Submitter: Labcorp Genetics (formerly Invitae)

familial colorectal cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0023113

Submitter: Ambry Genetics

microcephaly 30, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859342

Submitter: G2P

colorectal cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005575

Submitter: Ambry Genetics

microcephaly 30, primary, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859342

Submitter: Ambry Genetics

mosaic variegated aneuploidy syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000141

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly 30, primary, autosomal recessiveAR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Neurologic

Intervention: Cardiovascular; Endocrine

Rationale: The condition has been described as involving congenital cardiac anomalies, and awareness may allow early diagnosis and management; Growth hormone deficiency has been described, and awareness may allow medical management

Refs: 35044816

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BUB1 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 1373

not providedTotal: 269

BUB1-related disorderTotal: 9

Microcephaly 30, primary, autosomal recessiveTotal: 7

Colorectal cancerTotal: 3

Colorectal cancer with chromosomal instability, somaticTotal: 2

Carcinoma of colonTotal: 1

Inborn genetic diseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004336.5. 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			6 clinvar	434 clinvar	1 clinvar	441
missense	1 clinvar		938 clinvar	55 clinvar		994
nonsense			2 clinvar			2
start loss			1 clinvar			1
frameshift	2 clinvar	1 clinvar	5 clinvar			8
splice donor/acceptor (+/-2bp)	2 clinvar		9 clinvar			11
Total	5	1	961	489	1	1457

Highest pathogenic variant AF is 0.000014407482

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004336.5	RefSeq	NP_004327.1	25	MANE Select
ENST00000302759.11	Ensembl	ENSP00000302530.6	25	MANE Select
NM_001278616.2	RefSeq	NP_001265545.1	24	Standard
NM_001278617.2	RefSeq	NP_001265546.1	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Progesterone-mediated oocyte maturation - Homo sapiens (human)
Cell Cycle
ATM Signaling Network in Development and Disease

Biological Process

protein phosphorylation
apoptotic process
regulation of sister chromatid cohesion
mitotic cell cycle checkpoint
mitotic spindle assembly 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 nuclear chromosome outer kinetochore
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302759
Coding exons: 25
Length: 40417
Individuals with no LoFs: 125680
Homozygous LoFs: 0
Heterozygous LoFs: 68
Defined: 125748
p: 0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.848	500	556	0.899	0.0000267	7181
Missense (PolyPhen)		148	190.89	0.77531		2587
Synonymous	0.444	184	192	0.959	0.00000943	1958
Loss of Function	3.98	24	56.2	0.427	0.00000248	744

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00036	0.00036	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Required for centromeric enrichment of AUKRB in prometaphase. Plays an important role in defining SGO1 localization and thereby affects sister chromatid cohesion. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. {ECO:0000269|PubMed:10198256, ECO:0000269|PubMed:15020684, ECO:0000269|PubMed:15525512, ECO:0000269|PubMed:15723797, ECO:0000269|PubMed:16760428, ECO:0000269|PubMed:17158872, ECO:0000269|PubMed:19487456, ECO:0000269|PubMed:20739936}.;

Recessive Scores

pRec: 0.258

Intolerance Scores

LoFtool: 0.829
RVIS EVS: -1.22
RVIS percentile EVS: 5.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.832

Gene Damage Prediction

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