rs267605077
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000546.6(TP53):c.400T>G(p.Phe134Val) 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 17-7675212-A-C is Pathogenic according to our data. Variant chr17-7675212-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 988615.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 13, 2024 | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29979965]. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Li-Fraumeni syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 28, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 988615). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the TP53 protein (p.Phe134Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen
D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.;.
Vest4
MutPred
Loss of catalytic residue at F134 (P = 0.0523);Loss of catalytic residue at F134 (P = 0.0523);.;.;.;.;Loss of catalytic residue at F134 (P = 0.0523);.;Loss of catalytic residue at F134 (P = 0.0523);Loss of catalytic residue at F134 (P = 0.0523);Loss of catalytic residue at F134 (P = 0.0523);.;.;Loss of catalytic residue at F134 (P = 0.0523);.;.;.;.;Loss of catalytic residue at F134 (P = 0.0523);.;
MVP
MPC
1.9
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