chr17-7675238-T-C
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.376-2A>G variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TP53
NM_000546.6 splice_acceptor
NM_000546.6 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.01
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
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.
PP5
?
Variant 17-7675238-T-C is Pathogenic according to our data. Variant chr17-7675238-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.376-2A>G | splice_acceptor_variant | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.376-2A>G | splice_acceptor_variant | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461636Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727098
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461636
Hom.:
Cov.:
35
AF XY:
AC XY:
0
AN XY:
727098
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 13, 2024 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2023 | The c.376-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the TP53 gene. This alteration was identified once in a series of LFS families; however, clinical details were not provided (Wu CC et al. Hum. Genet., 2011 Jun;129:663-73). In addition, this alteration has been identified in individuals diagnosed with colorectal cancer, breast cancer, and B-CLL (Athanasakis E et al. Oncotarget, 2014 Dec;5:12635-45; Siraj AK et al. Hum. Genet., 2017 11;136:1431-1444; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1Other:1
not provided, no classification provided | in vitro | MutSpliceDB: a database of splice sites variants effects on splicing, NIH | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2022 | Canonical splice site variant expected to result in aberrant splicing and demonstrated to result in an in-frame loss of seven amino acids (Chappuis 1999, Athanasakis 2014); Functional assays performed on tumor cells harboring this variant found reduced or absent transactivation of typical TP53 targets (Chappuis 1999, Athanasakis 2014, Agnoletto 2015); Observed in a kindred reported to have features of Li-Fraumeni syndrome and also identified in individuals with breast, colorectal, or ovarian cancer (Kupryjanczyk 1993, Wu 2011, Siraj 2017, Li 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21305319, 27189670, 10567903, 11595686, 24729566, 26857262, 25544776, 28497333, 8506342, 28975465, 15510160, 33790576, 29751042, 30720243, 29752822, 29070607, 25587027, 10864200) - |
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 186236). Disruption of this splice site has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 21305319, 25544776, 25587027, 29752822; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). - |
Neoplasm of ovary Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Gallbladder cancer Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Oct 30, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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_AG_spliceai
Position offset: -23
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at