rs1057517841
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_003722.5(TP63):c.1727T>C(p.Ile576Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
TP63
NM_003722.5 missense
NM_003722.5 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
TP63 (HGNC:15979): (tumor protein p63) This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a domain SAM (size 66) in uniprot entity P63_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in NM_003722.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TP63
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
?
Variant 3-189890863-T-C is Pathogenic according to our data. Variant chr3-189890863-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 372540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP63 | NM_003722.5 | c.1727T>C | p.Ile576Thr | missense_variant | 13/14 | ENST00000264731.8 | |
TP63 | NM_001114980.2 | c.1445T>C | p.Ile482Thr | missense_variant | 11/12 | ENST00000354600.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP63 | ENST00000264731.8 | c.1727T>C | p.Ile576Thr | missense_variant | 13/14 | 1 | NM_003722.5 | P4 | |
TP63 | ENST00000354600.10 | c.1445T>C | p.Ile482Thr | missense_variant | 11/12 | 1 | NM_001114980.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
TP63-Related Spectrum Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 04, 2021 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 576 of the TP63 protein (p.Ile576Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant has been observed in individual(s) with ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (PMID: 11159940, 20156774, 30809829, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Ile541Thr, Ile537Thr, or Ile482Thr. ClinVar contains an entry for this variant (Variation ID: 372540). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TP63 protein function (PMID: 21652629, 21615690). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2015 | The I576T missense variant in the TP63 gene has been reported previously in association with Hay-Wells syndrome using alternate nomenclature (McGrath et al., 2001; Tomkova et al., 2010; Alessandro et al., 2013). This variant is present in the hydrophobic core of the SAM domain, and studies have shown that replacing the non-polar Isoleucine residue with a polar Threonine residue destabilizes the protein and affects its function (Sathyamurthy et al., 2011; Browne et al., 2011). Therefore, we interpret this variant as pathogenic. - |
TP63-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2023 | The TP63 c.1727T>C variant is predicted to result in the amino acid substitution p.Ile576Thr. This variant was reported in multiple individuals with Hay-Wells syndrome McGrath et al. 2001. PubMed ID: 11159940, reported as I541T; Tomková et al. 2010. PubMed ID: 20156774, reported as I537T; Serra et al. 2021. PubMed ID: 34583755). In vitro functional analysis indicates that this amino acid change impairs activity (Browne et al. 2011. PubMed ID: 21652629, reported as I537T). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;P;P;.
Vest4
MutPred
Gain of disorder (P = 0.0399);.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at