rs797044484
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_003722.5(TP63):c.1037C>G(p.Ala346Gly) 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
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.82
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 was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003722.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the TP63 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 73 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.2077 (below the threshold of 3.09). Trascript score misZ: 3.5096 (above the threshold of 3.09). GenCC associations: The gene is linked to Rapp-Hodgkin syndrome, ADULT syndrome, split hand-foot malformation 4, limb-mammary syndrome, premature ovarian failure 21, split hand-foot malformation, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 3-189868624-C-G is Pathogenic according to our data. Variant chr3-189868624-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 208418.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TP63 | NM_003722.5 | c.1037C>G | p.Ala346Gly | missense_variant | Exon 8 of 14 | ENST00000264731.8 | NP_003713.3 | |
| TP63 | NM_001114980.2 | c.755C>G | p.Ala252Gly | missense_variant | Exon 6 of 12 | ENST00000354600.10 | NP_001108452.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TP63 | ENST00000264731.8 | c.1037C>G | p.Ala346Gly | missense_variant | Exon 8 of 14 | 1 | NM_003722.5 | ENSP00000264731.3 | ||
| TP63 | ENST00000354600.10 | c.755C>G | p.Ala252Gly | missense_variant | Exon 6 of 12 | 1 | NM_001114980.2 | ENSP00000346614.5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Pathogenic:1
Feb 11, 2014
Laboratory of Human Genetics, Universidade de São Paulo
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research
The proband presents with EEC syndrome. Since the proband’s son does not have cleft lip/palate, his phenotype is similar to that of ADULT syndrome, which may not include clefting, breast hipoplasia or freckling. This clinical overlap could demonstrate that the distinctions between EEC and ADULT syndromes are somewhat artificial. The father of the proband allegedly presented only SHFM, without other manifestations. This could indicate that the mutation c.1037C>G might also be associated with nonsyndromic SHFM. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
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
P;P;P;P;P;P;P;P;.;P;.
Vest4
MutPred
Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Mutation Taster
=0/100
disease causing (ClinVar)
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