rs121908847
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_003722.5(TP63):c.1054A>G(p.Arg352Gly) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
TP63
NM_003722.5 missense
NM_003722.5 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 1.44
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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, 0.99
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP63 | NM_003722.5 | c.1054A>G | p.Arg352Gly | missense_variant | 8/14 | ENST00000264731.8 | |
TP63 | NM_001114980.2 | c.772A>G | p.Arg258Gly | missense_variant | 6/12 | ENST00000354600.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP63 | ENST00000264731.8 | c.1054A>G | p.Arg352Gly | missense_variant | 8/14 | 1 | NM_003722.5 | P4 | |
TP63 | ENST00000354600.10 | c.772A>G | p.Arg258Gly | missense_variant | 6/12 | 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: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Orofacial cleft 8 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria | May 08, 2022 | The c.1054A>G (p.Arg352Gly) TP63 variant has been reported in our laboratory in a 41-year-old woman with diagnosis of ectrodactyly and asymptomatic parents. Patient with two previous legal abortions due to fetuses affected by ectrodactyly, in one of them the presence of this heterozygous variant could be confirmed. It has been previously reported in non-syndromic cleft lip (PMID 16740912). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 6547). In silico analysis (CADD, Mutation Taster, SIFT, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. To date there are no functional/experimental studies that evaluate the impact on protein. In summary, c.1054A>G (p.Arg352Gly) TP63 variant meets our criteria to be classified as Variant of Uncertain Significance-Probably Pathogenic based upon its absence from controls, computational evidence of pathogenicity and and the clinical correlation in this family´s phenotype. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M;.;.;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D;.;D;.
Vest4
MutPred
Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);.;.;.;.;.;.;
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