Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.6 | MANE Select | 2512 nt | 143–1324 |
| NM_000546.4 | Alternative | 2586 nt | 198–1379 |
| NM_000546.2 | Alternative | 2629 nt | 252–1433 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.05 | -269 bp |
| Donor Loss (DL) | 0.01 | -401 bp |
| Acceptor Gain (AG) | 0.01 | 232 bp |
| Donor Gain (DG) | 0.0 | 283 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines: "Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)". The evidence for this variant shows a SpliceAI maximum score of 0.05, below any threshold for predicted splice disruption. Therefore, this criterion is not applied because no splice alteration is predicted.
PS1 (Not Applied)
According to standard ACMG guidelines: "PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows it is an intronic duplication at c.920-1, not causing an amino acid change identical to any known pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines: "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". No de novo or parental testing data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines: PS3 requires well-established functional studies demonstrating a damaging effect on protein function. No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines: "PS4: ≥8 points from proband observations (very strong) ...". No case-level or proband data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines: "PM1: Missense variants within TP53 hotspot codons (e.g., 175, 245, 248, 249, 273, 282)". This variant is an intronic duplication at a splice site, not a missense in a hotspot. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines: "PM2: Supporting level for allele frequency <0.00003 in gnomAD or another large database". The evidence for this variant shows absence from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines: "PM3: For recessive disorders, detected in trans with a pathogenic variant". TP53 is autosomal dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: "PM4: Protein length changes due to in-frame indels or stop-loss variants". This variant is intronic and does not change protein length directly. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines: "PM5: Missense variant at a residue where other pathogenic missense variants occur". This is not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines: "PM6: Assumed de novo, without confirmation of paternity/maternity". No de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines: "PP1: Cosegregation observed in family members". No family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: "PP2: Missense variant in a gene with low benign missense variation". This is an intronic duplication, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: "PP3: Intronic splice variants (excluding ±1,2 positions) with SpliceAI ≥0.2". This variant is at the −1 position and SpliceAI = 0.05. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines: "PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic". The variant is not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: "BA1: Stand-alone benign for FAF ≥0.001 in gnomAD subpopulations". The variant is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: "BS1: Filtering allele frequency ≥0.0003 but <0.001 in gnomAD". The variant is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines: "BS2: Observation in ≥8 healthy females ≥60 years old". No such observations exist. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: "BS3: Well-established functional studies show no loss of function". No functional assay data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines: "BS4: Lack of segregation in affected family members". No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: "BP1: Missense variant in a gene for which only truncating variants cause disease". TP53 disease mechanism includes missense dominant-negative effects. Also, this is not a missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines: "BP2: Observed in trans with a pathogenic variant for a dominant disorder". No trans observations reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: "BP3: In-frame deletions/insertions in repetitive regions without a known function". This variant is a single nucleotide intronic duplication not in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines: "BP4: Silent or intronic variants outside ±1,2 positions with SpliceAI ≤0.1". This variant is at −1 position. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines: "BP7: Synonymous or intronic ≥+7/−21 positions with no predicted splicing impact". This variant is at the canonical −1 splice position. Therefore, this criterion is not applied.