rs34361146
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000546.6(TP53):c.920-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000546.6 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.920-5C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.920-5C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152128Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251470Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135910
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727244
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152246Hom.: 1 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74432
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 17, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 08, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2022 | Variant summary: TP53 c.920-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 251470 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.920-5C>T in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 20, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2018 | - - |
Li-Fraumeni syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at