TP63

tumor protein p63, the group of MicroRNA protein coding host genes

Basic information

Region (hg38): 3:189631388-189897276

Previous symbols: [ "TP73L", "TP53L", "TP53CP" ]

Links

ENSG00000073282 ∙ NCBI:8626 ∙ OMIM:603273 ∙ HGNC:15979 ∙ Uniprot:Q9H3D4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (Definitive), mode of inheritance: AD
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (Definitive), mode of inheritance: AD
• Rapp-Hodgkin syndrome (Definitive), mode of inheritance: AD
• ADULT syndrome (Definitive), mode of inheritance: AD
• limb-mammary syndrome (Definitive), mode of inheritance: AD
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (Definitive), mode of inheritance: AD
• ADULT syndrome (Supportive), mode of inheritance: AD
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (Supportive), mode of inheritance: AD
• EEC syndrome (Supportive), mode of inheritance: AD
• split hand-foot malformation (Supportive), mode of inheritance: AD
• limb-mammary syndrome (Supportive), mode of inheritance: AD
• split hand-foot malformation 4 (Moderate), mode of inheritance: AD
• premature ovarian failure 21 (Strong), mode of inheritance: AD
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Split-hand/foot malformation 4; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3; Limb-mammary syndrome; Rapp-Hodgkin syndrome; ADULT syndrome; Ankyloblepharon-ectodermal defects-cleft lip/palate; Orofacial cleft 8; Premature ovarian failure 21	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Audiologic/Otolaryngologic; Craniofacial; Dental; Dermatologic; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Obstetric	5713637; 946410; 3366140; 9443880; 10535733; 9973291; 10886756; 10839977; 11528512; 11159940; 11462173; 11929852; 12838557; 12939657; 14684701; 12766194; 15200513; 16688749; 16740912; 17041931; 16724007; 17609671; 17431922; 18627043; 19239083; 18603493; 19697430; 19353643; 19676059; 19530185; 21204238; 21990121; 22065540; 22065614; 22069181; 22430731; 22574117; 22607287; 22740388; 29500247; 30924587; 35801529; 36856110

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TP63 gene.

• TP63-Related Spectrum Disorders (420 variants)
• not provided (173 variants)
• Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (112 variants)
• Orofacial cleft 8 (93 variants)
• 7 conditions (32 variants)
• not specified (21 variants)
• TP63-related condition (18 variants)
• Inborn genetic diseases (13 variants)
• Ectrodactyly (9 variants)
• Cleft Lip +/- Cleft Palate, Autosomal Dominant (9 variants)
• Split hand-foot malformation 4 (8 variants)
• ADULT syndrome (6 variants)
• Rapp-Hodgkin ectodermal dysplasia syndrome (4 variants)
• Limb-mammary syndrome (3 variants)
• Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (3 variants)
• ADULT syndrome;Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (1 variants)
• Auditory neuropathy (1 variants)
• Skeletal dysplasia (1 variants)
• Muscular dystrophy (1 variants)
• Furrowed tongue (1 variants)
• TP63-related ectodermal dysplasia (1 variants)
• Ankyloblepharon filiforme adnatum-cleft palate syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TP63 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			3	71	6	80
missense	24	37	158	9	5	233
nonsense	3	4	3	1		11
start loss	1	1	1			3
frameshift	5	2	1			8
inframe indel	1	4	3			8
splice donor/acceptor (+/-2bp)	1					1
splice region			8	10	1	19
non coding			41	73	70	184
Total	35	48	210	154	81

Highest pathogenic variant AF is 0.0000132

Variants in TP63

This is a list of pathogenic ClinVar variants found in the TP63 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-189631429-C-T		Orofacial cleft 8 • TP63-Related Spectrum Disorders • Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	Uncertain significance (Jan 12, 2018)
3-189631451-C-T		TP63-Related Spectrum Disorders • Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 • Orofacial cleft 8	Uncertain significance (Jan 12, 2018)
3-189631458-A-T		Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 • TP63-Related Spectrum Disorders • Orofacial cleft 8	Benign (Jan 13, 2018)
3-189631478-T-C		Orofacial cleft 8 • TP63-Related Spectrum Disorders • Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	Uncertain significance (Jan 13, 2018)
3-189631513-G-C		Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 • TP63-Related Spectrum Disorders • Orofacial cleft 8	Uncertain significance (Apr 27, 2017)
3-189631518-G-T		Furrowed tongue	Likely pathogenic (Jul 14, 2021)
3-189631534-C-T		TP63-Related Spectrum Disorders	Uncertain significance (Nov 24, 2023)
3-189631535-G-T		TP63-Related Spectrum Disorders • 7 conditions • TP63-related disorder	Benign/Likely benign (Dec 06, 2022)
3-189631541-C-G		TP63-Related Spectrum Disorders	Uncertain significance (Aug 10, 2022)
3-189631542-C-T		TP63-Related Spectrum Disorders	Likely benign (Oct 13, 2022)
3-189631550-A-C		TP63-Related Spectrum Disorders	Uncertain significance (Jun 28, 2023)
3-189631562-A-G		TP63-Related Spectrum Disorders	Uncertain significance (Oct 13, 2023)
3-189631565-C-G		TP63-Related Spectrum Disorders • 7 conditions	Uncertain significance (Oct 13, 2023)
3-189631568-A-G		Premature ovarian insufficiency	Uncertain significance (Mar 01, 2022)
3-189631576-C-T		TP63-Related Spectrum Disorders • Orofacial cleft 8 • Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	Uncertain significance (Jan 13, 2018)
3-189631577-G-A		TP63-Related Spectrum Disorders • 7 conditions	Uncertain significance (Aug 11, 2023)
3-189631595-A-G		TP63-Related Spectrum Disorders	Likely benign (Aug 14, 2023)
3-189631802-C-T			Likely benign (Sep 26, 2018)
3-189638472-T-C		TP63-Related Spectrum Disorders	Benign (Feb 01, 2024)
3-189639813-T-C		TP63-Related Spectrum Disorders	Benign (Feb 01, 2024)
3-189639813-TG-CA		TP63-Related Spectrum Disorders	Benign (Jan 04, 2024)
3-189656444-G-T			Benign (May 15, 2021)
3-189656568-T-A			Benign (May 15, 2021)
3-189656808-C-T			Likely benign (Sep 07, 2021)
3-189656853-G-C			Benign (May 15, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TP63	protein_coding	protein_coding	ENST00000264731	14	265864

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00272	125721	0	27	125748	0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.21	290	417	0.696	0.0000262	4505
Missense in Polyphen		78	179.41	0.43477		1883
Synonymous	-0.994	170	154	1.10	0.0000103	1302
Loss of Function	5.08	5	39.4	0.127	0.00000237	393

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000904	0.0000904
Ashkenazi Jewish	0.00119	0.00119
East Asian	0.00	0.00
Finnish	0.000277	0.000277
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. Isoform 2 activates RIPK4 transcription. May be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes. Involved in Notch signaling by probably inducing JAG1 and JAG2. Plays a role in the regulation of epithelial morphogenesis. The ratio of DeltaN-type and TA*-type isoforms may govern the maintenance of epithelial stem cell compartments and regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm. Required for limb formation from the apical ectodermal ridge. Activates transcription of the p21 promoter. {ECO:0000269|PubMed:11641404, ECO:0000269|PubMed:12374749, ECO:0000269|PubMed:12446779, ECO:0000269|PubMed:12446784, ECO:0000269|PubMed:20123734, ECO:0000269|PubMed:22197488, ECO:0000269|PubMed:9774969}.
• Disease: DISEASE: Acro-dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome) [MIM:103285]: A form of ectodermal dysplasia. Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. ADULT syndrome involves ectrodactyly, syndactyly, finger- and toenail dysplasia, hypoplastic breasts and nipples, intensive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia and loss of permanent teeth. ADULT syndrome differs significantly from EEC3 syndrome by the absence of facial clefting. Inheritance is autosomal dominant. {ECO:0000269|PubMed:11929852}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) [MIM:106260]: An autosomal dominant condition characterized by congenital ectodermal dysplasia with coarse, wiry, sparse hair, dystrophic nails, slight hypohidrosis, scalp infections, ankyloblepharon filiform adnatum, maxillary hypoplasia, hypodontia and cleft lip/palate. {ECO:0000269|PubMed:11159940}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3) [MIM:604292]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is an autosomal dominant syndrome characterized by ectrodactyly of hands and feet, ectodermal dysplasia and facial clefting. {ECO:0000269|PubMed:10535733, ECO:0000269|PubMed:10839977, ECO:0000269|PubMed:11462173, ECO:0000269|PubMed:12838557}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Split-hand/foot malformation 4 (SHFM4) [MIM:605289]: A limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients have been found to have mental retardation, ectodermal and craniofacial findings, and orofacial clefting. {ECO:0000269|PubMed:10839977, ECO:0000269|PubMed:11462173}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Limb-mammary syndrome (LMS) [MIM:603543]: Characterized by ectrodactyly, cleft palate and mammary-gland abnormalities. {ECO:0000269|PubMed:11462173}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in TP63 are a cause of cervical, colon, head and neck, lung and ovarian cancers.; DISEASE: Ectodermal dysplasia, Rapp-Hodgkin type (EDRH) [MIM:129400]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Characterized by the combination of anhidrotic ectodermal dysplasia, cleft lip, and cleft palate. The clinical syndrome is comprised of a characteristic facies (narrow nose and small mouth), wiry, slow-growing, and uncombable hair, sparse eyelashes and eyebrows, obstructed lacrimal puncta/epiphora, bilateral stenosis of external auditory canals, microsomia, hypodontia, cone-shaped incisors, enamel hypoplasia, dystrophic nails, and cleft lip/cleft palate. {ECO:0000269|PubMed:12766194, ECO:0000269|PubMed:12939657, ECO:0000269|PubMed:15200513, ECO:0000269|PubMed:16740912}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Non-syndromic orofacial cleft 8 (OFC8) [MIM:129400]: A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: MicroRNAs in cancer - Homo sapiens (human);TP53 Network;Apoptosis;Hair Follicle Development- Induction (Part 1 of 3);Apoptotic Signaling Pathway;Hypothetical Craniofacial Development Pathway;Gene expression (Transcription);Generic Transcription Pathway;TP53 Regulates Transcription of Cell Death Genes;RNA Polymerase II Transcription;Activation of PUMA and translocation to mitochondria;Activation of BH3-only proteins;Intrinsic Pathway for Apoptosis;Apoptosis;Programmed Cell Death;p73 transcription factor network;TP53 Regulates Metabolic Genes;TP53 Regulates Transcription of Genes Involved in Cytochrome C Release;TP53 Regulates Transcription of Caspase Activators and Caspases;TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain;Validated transcriptional targets of TAp63 isoforms;Regulation of TP53 Activity through Association with Co-factors;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Direct p53 effectors;Validated transcriptional targets of deltaNp63 isoforms;TP53 Regulates Transcription of Death Receptors and Ligands (Consensus)

Recessive Scores

• pRec: 0.571

Intolerance Scores

• loftool: 0.00668
• rvis_EVS: -0.91
• rvis_percentile_EVS: 9.96

Haploinsufficiency Scores

• pHI: 0.910
• hipred: Y
• hipred_score: 0.749
• ghis: 0.587

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.866

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Trp63
• Phenotype: immune system phenotype; renal/urinary system phenotype; skeleton phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; normal 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); neoplasm; embryo phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region 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); taste/olfaction phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: tp63
• Affected structure: peridermal cell
• Phenotype tag: abnormal
• Phenotype quality: increased size

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;replicative cell aging;skeletal system development;establishment of planar polarity;epithelial cell development;chromatin remodeling;apoptotic process;Notch signaling pathway;spermatogenesis;ectoderm and mesoderm interaction;cell population proliferation;proximal/distal pattern formation;multicellular organism aging;epidermal cell division;regulation of epidermal cell division;positive regulation of keratinocyte proliferation;keratinocyte differentiation;polarized epithelial cell differentiation;hair follicle morphogenesis;negative regulation of intracellular estrogen receptor signaling pathway;embryonic forelimb morphogenesis;embryonic hindlimb morphogenesis;post-anal tail morphogenesis;odontogenesis of dentin-containing tooth;intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator;regulation of apoptotic process;regulation of cysteine-type endopeptidase activity involved in apoptotic process;skin morphogenesis;negative regulation of keratinocyte differentiation;positive regulation of osteoblast differentiation;positive regulation of Notch signaling pathway;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;sympathetic nervous system development;female genitalia morphogenesis;protein homotetramerization;neuron apoptotic process;cloacal septation;prostatic bud formation;squamous basal epithelial stem cell differentiation involved in prostate gland acinus development;establishment of skin barrier;positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway;regulation of signal transduction by p53 class mediator;positive regulation of somatic stem cell population maintenance;cranial skeletal system development;positive regulation of fibroblast apoptotic process;negative regulation of mesoderm development
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;cytoplasm;mitochondrion;rough endoplasmic reticulum;Golgi apparatus;cytosol;dendrite;protein-containing complex
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;p53 binding;DNA binding;chromatin binding;damaged DNA binding;double-stranded DNA binding;DNA-binding transcription factor activity;protein binding;identical protein binding;sequence-specific DNA binding;transcription regulatory region DNA binding;metal ion binding;WW domain binding;MDM2/MDM4 family protein binding