rs11575996
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000546.6(TP53):c.993G>T(p.Gln331His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
TP53
NM_000546.6 missense, splice_region
NM_000546.6 missense, splice_region
Scores
2
9
8
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.38
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 8 ACMG points.
PM1
In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 62 pathogenic changes around while only 6 benign (91%) in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.993G>T | p.Gln331His | missense_variant, splice_region_variant | 9/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.993G>T | p.Gln331His | missense_variant, splice_region_variant | 9/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2023 | This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the c.993G nucleotide in the TP53 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22653678, 29324801, 33674644). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 19454241). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 331 of the TP53 protein (p.Gln331His). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;D;D;T;T;.;.;.;T;T;.;T;T;D;D;T;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;D;D;T;T;D;D;T;T;T;D;D;D;D;D;T;T;T;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;.;T;.;.;D;D;.;.;T;.;.;D
Sift4G
Uncertain
D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
Polyphen
0.026, 0.11, 0.013
.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4
MutPred
Gain of methylation at R333 (P = 0.0465);.;.;.;.;.;.;.;Gain of methylation at R333 (P = 0.0465);.;Gain of methylation at R333 (P = 0.0465);Gain of methylation at R333 (P = 0.0465);Gain of methylation at R333 (P = 0.0465);.;.;Gain of methylation at R333 (P = 0.0465);.;.;.;
MVP
MPC
0.067
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at