rs730881997
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000546.6(TP53):c.370T>G(p.Cys124Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C124S) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 5.75
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 6 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000546.6
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.937
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.370T>G | p.Cys124Gly | missense_variant | 4/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.370T>G | p.Cys124Gly | 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: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2022 | The p.C124G variant (also known as c.370T>G), located in coding exon 3 of the TP53 gene, results from a T to G substitution at nucleotide position 370. The cysteine at codon 124 is replaced by glycine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have a partial loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0005% (greater than 200000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;.;D;D;.;D;D;D;D;D;T;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
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
Uncertain
D;D;.;D;.;.;D;D;.;.;D;.;D;.;D
REVEL
Pathogenic
Sift
Benign
T;T;.;T;.;.;T;T;.;.;T;.;D;.;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T;T;.;D;.
Polyphen
P;.;.;P;.;P;B;P;.;.;P;.;P;.;.
Vest4
MutPred
Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);.;Gain of disorder (P = 0.0144);.;Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);.;.;Gain of disorder (P = 0.0144);.;Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);
MVP
MPC
1.8
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