chr17-7675215-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000504937.5(TP53):c.1A>G(p.Met1?) variant causes a start lost 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: 33)
Consequence
TP53
ENST00000504937.5 start_lost
ENST00000504937.5 start_lost
Scores
1
9
8
Clinical Significance
Conservation
PhyloP100: 3.47
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.397A>G | p.Met133Val | missense_variant | 5/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.397A>G | p.Met133Val | missense_variant | 5/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250826Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135576
GnomAD3 exomes
AF:
AC:
1
AN:
250826
Hom.:
AF XY:
AC XY:
0
AN XY:
135576
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 23, 2019 | 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. A different missense substitution at this codon (p.Met133Thr) has been reported in families affected with Li-Fraumeni syndrome (PMID: 1933902, 17606709), and it has been shown to impair the transcriptional transactivation activity of the TP53 protein in experimental studies (PMID: 12826609, 17606709, 20128691, 21343334). This suggests that the methionine residue is critical for TP53 protein function and that other missense substitutions at this position may also be damaging. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 528246). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 133 of the TP53 protein (p.Met133Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N;.
REVEL
Uncertain
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
B;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.;.
Vest4
MutPred
Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);.;.;.;.;Loss of catalytic residue at M133 (P = 9e-04);.;Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);.;.;Loss of catalytic residue at M133 (P = 9e-04);.;.;.;.;Loss of catalytic residue at M133 (P = 9e-04);.;
MVP
MPC
0.67
ClinPred
T
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