rs1555526131
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.476C>T(p.Ala159Val) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 8.15
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 Pathogenic. Variant got 16 ACMG points.
PM1
In a strand (size 9) in uniprot entity P53_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 17-7675136-G-A is Pathogenic according to our data. Variant chr17-7675136-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7675136-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.476C>T | p.Ala159Val | missense_variant | 5/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.476C>T | p.Ala159Val | missense_variant | 5/11 | 1 | NM_000546.6 | ENSP00000269305.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 14, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20505364, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 14, 2023 | ClinVar contains an entry for this variant (Variation ID: 458545). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 159 of the TP53 protein (p.Ala159Val). This variant disrupts the p.Ala159 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27545002, 29070607, 32658383). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. For these reasons, this variant has been classified as Pathogenic. - |
Adrenocortical carcinoma, hereditary Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2021 | Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired growth suppression activities (Kato 2003, Kotler 2018).; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17724467, 20505364, 22862161, 12826609, 16322298, 29979965, 15510160) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The p.A159V pathogenic mutation (also known as c.476C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 476. The alanine at codon 159 is replaced by valine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Neoplasm Other:1
-, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;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;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G
Uncertain
D;D;T;T;T;D;D;D;D;D;D;T;D;D;D;D;T;.;.
Polyphen
D;.;.;.;.;.;P;.;P;B;P;.;.;P;.;.;.;D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.1082);Gain of MoRF binding (P = 0.1082);.;.;.;.;Gain of MoRF binding (P = 0.1082);.;Gain of MoRF binding (P = 0.1082);Gain of MoRF binding (P = 0.1082);Gain of MoRF binding (P = 0.1082);.;.;Gain of MoRF binding (P = 0.1082);.;.;.;.;Gain of MoRF binding (P = 0.1082);
MVP
MPC
1.6
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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