rs587781504
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000546.6(TP53):c.314G>T(p.Gly105Val) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G105D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 6.36
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 10 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000546.6
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-7676056-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 17-7676055-C-A is Pathogenic according to our data. Variant chr17-7676055-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 634708.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.314G>T | p.Gly105Val | missense_variant | 4/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.314G>T | p.Gly105Val | missense_variant | 4/11 | 1 | NM_000546.6 | P1 |
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: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research | Jun 06, 2022 | - - |
Ovarian neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;D;.;.;.;.;.;.;D;.;.;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
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
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;T;.;D;.
Polyphen
D;.;.;D;.;D;D;D;.;.;D;.;.;D;.;.
Vest4
MutPred
Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);.;Loss of disorder (P = 0.0517);.;Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);.;.;Loss of disorder (P = 0.0517);.;Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);Loss of disorder (P = 0.0517);
MVP
MPC
1.9
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
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at