TP63

Gene Facts

• HGNC Symbol: TP63 (HGNC:15979)
• HGNC Name: tumor protein p63
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: TP73L, TP53L, TP53CP
• Alias symbols: p51, SHFM4, EEC3, p63, p73L, OFC8, KET, p73H, NBP, p53CP, p40
• %HI: 1.11
• pLI: 1
• LOEUF: 0.3
• Cytoband: 3q28
• Genomic Coordinates:

  GRCh37/hg19:	chr3:189314535-189615065
  GRCh38/hg38:	chr3:189596746-189897276

• MANE Select Transcript: NM_003722.5 ENST00000264731.8
• MANE Plus Clinical Transcript(s):

  NM_001114980.2 ENST00000354600.10 (Read more about MANE Plus Clinical)

• 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 JAG... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-10639
• ClinGen Curation ID: CCID:008028
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 05/10/2023

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• cleft lip/palate

HI Evidence

• PUBMED: 30850703
  Khandelwal et al 2019 (PMID: 30850703) identified one frameshift variant in exon 4 and one stopgain variant in exon 8 in two individuals with cleft lip/palate (CL/P) using targeted molecular inversion probes. One was inherited from an unaffected parent; inheritance of the other variant could not be determined. In addition to the truncating variants (and other missense variants) three deletions identified by genomic microarray involving TP63 were identified in three families with orofacial clefting, hypodontia, nail and skin abnormalities, and choanal atresia. Two deletions segregated in their families in a total of 7 additional relatives tested. One deletion arose de novo. The deletions ranged in size from 528-880kb and included additional coding genes.
• PUBMED: 29130604
  Wenger et al 2018 (PMID: 29130604) describes a family co-segregating a frameshift variant in exon 10 identified by targeted sequencing of TP63 in three family members from two generations. A father and one of his son had a CL/P, whereas a second son had no CL/P, but did have a larygeal cleft.
• PUBMED: 33622322
  Xu et al 2021 (PMID: 33622322) describes a three generation family with CL/P. All affected individuals carried a frameshift variant in exon 10 identified by whole exome sequencing. One carrier was unaffected.
• PUBMED: 29500247
  Basha et al 2018 (PMID: 29500247) describes a father/son duo with CL/P. Whole exome sequencing identified a frameshift variant in exon 6 identified by whole exome sequencing.
• PUBMED: 26117585
  Ponzi et al. 2015 (PMID: 26117585). 1.9 Mb deletion over TP53 and 7 other protein genes identified in man and his son. The father was mildly effected, but did have a a cleft pallet and mild learning difficulties. The child was diagnosed with mild psychomotor and speech delay, facial dysmorphism and postaxial polydactyly.
• PUBMED: 11462173
  van Bokhoven et al. (2001) describe TP63 mutations in a series of 43 individuals with EEC syndrome, 35 individuals with isolated SHFM, and three families with LMS. Three frameshift mutations were detected; one in an individual diagnosed with EEC, and the other two in individuals with features more consistent with LMS. All three frameshift mutations affect only the p63α isotypes, which have dominant-negative effects on transactivation, whereas the β and γ isotypes may be normally produced. The two frameshift mutations in exon 13 are predicted to yield similar protein products with premature truncations in the SAM domain, whereas the frameshift in exon 14 does not affect the SAM domain. From the manuscript: A single nonsense mutation was reported in an individual with isolated SHFM (Q634X), "as [was] a mutation in the 3′ splice site in intron 4. This splice-site mutation is likely to give rise to alternative splicing rather than to skipping of exon 5, because the latter is likely to be a loss-of-function event. Three nucleotides in front of the normal 3′ splice site is a potential splice-acceptor site (fig. 2). Use of this alternative site would lead to insertion of a proline amino acid at position 233 in the DNA-binding domain. Indeed, this alternative splicing route was used for this mutation in an exon-trapping assay (fig. 2). Although unlikely, we cannot formally exclude the possibility that this mutation generates a haploinsufficiency in the patient." The authors pose that haploinsufficiency of TP63 is not believed to cause features of EEC, as a previously reported individual (Chitayat et al. 1996) with a terminal 3q27 deletion did not have features of the syndrome; these authors performed FISH on a sample from this individual to confirm the absence of TP63.

• HI Evidence Comments: Pathogenic variation in TP63 is monoallelic and is associated with multiple clinical entities with overlapping phenotypes. These include Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome (MIM: 103285), Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3; MIM: 604292), Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (also known as Hay-Wells syndrome; MIM: 106260, and includes Rapp-Hodgkin syndrome; MIM:129400), Limb-mammary syndrome (LMS; MIM: 603543), Split-hand/foot malformation 4 (SHFM4; MIM: 605289), and Orofacial cleft 8 (OFC8; MIM: 129400). TP63 encodes a transcription factor highly expressed in skin, and through alternative splicing, generates numerous transcript isoforms resulting in peptides with unique amino and carboxy terminal domains. These isoforms differ in transcriptional transactivation and transinhibitory domains, but constitutively share the same DNA binding and oligomerization domains (exons 4-10 on NM_003722.5). The majority of pathogenic variation reported to date is thought to act via a gain-of-function mechanism, and is found in the form of missense variants located throughout the gene, or truncating variants located in non-constitutively expressed exons (e.g. truncating variants in the 3' end have been observed in SHFM, LMS, and AEC). However, a small number of truncating variants located in the constitutively expressed exons have been described and are associated with non-syndromic cleft lip/palate (CL/P; OFC8); these variants are the subject of this curation. Larger deletions encompassing TP63 identified by genomic microarray have also been observed in a small number of individuals including those with 3q27.3 microdeletion syndrome (PMID: 24133203). While CL/P is a common finding in these individuals, unaffected carriers have been observed in families, suggesting incomplete penetrance of this malformation. Additionally, these literature observations, when combined with internal data from ARUP Laboratories, suggest that while larger deletions are associated with a more severe developmental presentation overall (developmental delay with additional variable congenital anomalies with or without CL/P), CL/P is more commonly identified in individuals with smaller deletions over TP63, suggest position-dependent effects. In summary, while evidence suggest that monoallelic loss of TP63 leads to a risk of CL/P, due to incomplete penetrance of this feature and paucity of focal deletions in the literature, it is unknown at this time if the molecular disease mechanisms of TP63-related disorders include haploinsufficiency. Brunner et al. (PMID:12070241) propose a "partial loss of function in combination with dominant gain or change of function defects."

Triplosensitivity (TS) Score Details

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