17-7675181-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000546.6(TP53):​c.431A>G​(p.Gln144Arg) 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 (★).

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.04
Variant links:
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 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, 0.89

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.431A>G p.Gln144Arg missense_variant Exon 5 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.431A>G p.Gln144Arg missense_variant Exon 5 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1
Jan 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 144 of the TP53 protein (p.Gln144Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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. -

Prostate cancer, hereditary, 1 Uncertain:1
Jan 01, 2024
Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.9
.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.0
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0050
D;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;D;D;D;.
Sift4G
Uncertain
0.0090
D;D;T;T;T;D;D;D;D;D;D;T;D;D;D;D;T;.;.;T
Polyphen
1.0
D;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D;.;.
Vest4
0.72
MutPred
0.74
Loss of ubiquitination at K139 (P = 0.059);Loss of ubiquitination at K139 (P = 0.059);.;.;.;.;Loss of ubiquitination at K139 (P = 0.059);.;Loss of ubiquitination at K139 (P = 0.059);Loss of ubiquitination at K139 (P = 0.059);Loss of ubiquitination at K139 (P = 0.059);.;.;Loss of ubiquitination at K139 (P = 0.059);.;.;.;.;Loss of ubiquitination at K139 (P = 0.059);.;
MVP
0.96
MPC
1.7
ClinPred
0.95
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.75
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7578499; COSMIC: COSV52675618; COSMIC: COSV52675618; API