TUBB1

protein-coding

tubulin beta 1 class VI, the group of Tubulins

Gene summary

This gene encodes a member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is specifically expressed in platelets and megakaryocytes and may be involved in proplatelet production and platelet release. A mutations in this gene is associated with autosomal dominant macrothrombocytopenia. Two pseudogenes of this gene are found on chromosome Y.[provided by RefSeq, Jul 2010]

MANE transcript

NM_030773.4

Inheritance

ClinVar variants

P:24U:215B:94

Top phenotype

Macrothrombocytopenia, isolated, autosomal dominant 1

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr20:59,019,429-59,026,654

External References & Databases

Ensembl (ENSG00000101162)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

macrothrombocytopenia, isolated, 1, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0800047

Submitter: Illumina

macrothrombocytopenia, isolated, 1, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800047

Submitter: ClinGen

TUBB1 was first reported in relation to autosomal dominant macrothrombocytopenia in 2009 (Kunishima S, et al., 2009, PMID: 18849486). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 29 unique variants (mostly missense, but also nonsense, splice site, and frameshifts) have been reported in this gene in at least 29 probands in 11 publications (PMIDs: 18849486, 24344610, 27479822, 27905099, 30854628, 31565851, 28983057, 31064749, 32757236, 33217855, 32892537). Variants segregated with disease in an additional 20 family members. This gene-disease relationship is supported by restricted expression of β1 tubulin in platelets and megakaryocytes, where it appears late in differentiation and localizes to microtubule shafts and coils within proplatelets (PMID: 10942379), functional alteration in both patient and non-patient cells in which variant TUBB1 caused impaired megakaryocyte fragmentation and diminished proplatelet generation (PMIDs: 18849486, 30854628), and three model systems in cell culture (PMID: 24344610), mouse (PMID: 24344610), and canine (PMID: 18466252) with recapitulation of human disease. In summary TUBB1 is definitively associated with autosomal dominant macrothrombocytopenia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

macrothrombocytopenia, isolated, 1, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800047

Submitter: Labcorp Genetics (formerly Invitae)

macrothrombocytopenia, isolated, 1, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800047

Submitter: PanelApp Australia

autosomal dominant macrothrombocytopeniaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: Orphanet

Clinical Genomic Database (CGD)

Macrothrombocytopenia, isolated, autosomal dominant 1AD

Manifestation: Hematologic

Intervention: General

Rationale: The clinical significance is unclear

Refs: 15956286; 18849486

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBB1 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 280

not specifiedTotal: 66

TUBB1-related disorderTotal: 50

Macrothrombocytopenia, isolated, 1, autosomal dominantTotal: 50

Inborn genetic diseasesTotal: 23

MacrothrombocytopeniaTotal: 13

ThrombocytopeniaTotal: 11

Abnormal bleedingTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030773.4. 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				72 clinvar	1 clinvar	73
missense	1 clinvar	7 clinvar	196 clinvar	18 clinvar	2 clinvar	224
nonsense	2 clinvar	7 clinvar	4 clinvar	1 clinvar		14
start loss			1 clinvar			1
frameshift		5 clinvar	10 clinvar			15
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	3	21	215	91	3	333

Highest pathogenic variant AF is 0.000056380613

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030773.4	RefSeq	NP_110400.1	4	MANE Select
ENST00000217133.2	Ensembl	ENSP00000217133.1	4	MANE Select
ENST00001133605.1	Ensembl	ENSP00000801581.1	4	Standard
XM_017028085.2	RefSeq	XP_016883574.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
Gap junction - Homo sapiens (human)
Pathogenic Escherichia coli infection - Homo sapiens (human)
Docetaxel Action Pathway
Paclitaxel Action Pathway

Biological Process

microtubule cytoskeleton organization
mitotic cell cycle
microtubule-based process
spindle assembly

Molecular Function

GTPase activity
structural constituent of cytoskeleton
GTP binding

Cellular Component

cytoplasm
microtubule
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217133
Coding exons: 4
Length: 7401
Individuals with no LoFs: 125599
Homozygous LoFs: 0
Heterozygous LoFs: 149
Defined: 125748
p: 0.000593

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00274	272	272	1.00	0.0000179	3008
Missense (PolyPhen)		157	159.84	0.98222		1700
Synonymous	-0.253	119	116	1.03	0.00000892	878
Loss of Function	0.580	12	14.4	0.835	8.65e-7	142

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.0062	0.0062	notable
East Asian	0.00054	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.00023	0.00020	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). {ECO:0000250}.;
Disease: DISEASE: Macrothrombocytopenia, autosomal dominant, TUBB1-related (MAD-TUBB1) [MIM:613112]: A congenital blood disorder characterized by increased platelet size and decreased number of circulating platelets. {ECO:0000269|PubMed:18849486}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.252

Intolerance Scores

LoFtool: 0.420
RVIS EVS: 0.87
RVIS percentile EVS: 88.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.938

Gene Damage Prediction

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