3-189864392-A-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_003722.5(TP63):c.740A>G(p.His247Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H247Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003722.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP63 | NM_003722.5 | c.740A>G | p.His247Arg | missense_variant | 5/14 | ENST00000264731.8 | |
TP63 | NM_001114980.2 | c.458A>G | p.His153Arg | missense_variant | 3/12 | ENST00000354600.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP63 | ENST00000264731.8 | c.740A>G | p.His247Arg | missense_variant | 5/14 | 1 | NM_003722.5 | P4 | |
TP63 | ENST00000354600.10 | c.458A>G | p.His153Arg | missense_variant | 3/12 | 1 | NM_001114980.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
TP63-Related Spectrum Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 27, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p. His247 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16691622, 19663851). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 208163). This missense change has been observed in individual(s) with ectrodactyly–ectodermal dysplasia–cleft lip ⁄ palate (EEC) syndrome (PMID: 19903181, 26380986). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 247 of the TP63 protein (p.His247Arg). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2019 | Has been reported (as H208R due to use of alternate nomenclature) in two unrelated individuals with Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome (Clements et al., 2010); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis, which includes includes splice predictors, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26380986, 19903181, 29620206, 32881366) - |
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília | Apr 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at