Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
TP53
Final classification
VUS
TP53 c.-29+100dup · p.?
TP53

NM_000546.6:c.-29+100dup is an intronic duplication at position +100 of intron 1 in TP53. SpliceAI predicts no splicing impact (max delta score = 0.00).

Gene
TP53
Transcript
NM_000546.6
HGVS · transcript:coding
NM_000546.6:c.-29+100dup
Consequence
N/A
GRCh38
chr17:7687276 C>CT
GRCh37
chr17:7590594 C>CT
Basis Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 supporting benign (-1) + BP7 supporting benign (-1) = -1 points, which maps to VUS.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + BP4 supporting benign (-1) + BP7 supporting benign (-1) = -1 points, which maps to VUS.
Classification rationale
PM2 BP4BP7 VUS
TP53 c.-29+100dup

NM_000546.6:c.-29+100dup is an intronic duplication at position +100 of intron 1 in TP53. SpliceAI predicts no splicing impact (max delta score = 0.00).1 The variant is present in gnomAD v4.1 at an extremely low frequency (AF=2.26×10⁻⁵, 9/398,376 alleles; grpmax FAF=2.07×10⁻⁵), meeting PM2_Supporting per TP53 VCEP thresholds (total AF < 0.00003; subpopulation AF < 0.00004).2 As an intronic variant outside the core splice motif with SpliceAI score ≤ 0.1, BP4_Supporting is met per the TP53 VCEP PP3/BP4/BP7 flowchart.3 As an intronic variant at position +100 (beyond +7) with SpliceAI predicting no splice impact, BP7_Supporting is met per the TP53 VCEP specification (Walker et al. 2023, PMID:37352859).4 The variant is absent from ClinVar and COSMIC and has not been reported in the literature. No proband, segregation, de novo, or functional data are available.5 All other ACMG/AMP criteria are either not applicable (intronic variant outside scope of VCEP rules for missense/null/functional criteria) or not assessed due to absence of clinical data.

PM2 + BP4 + BP7 VUS
3 spliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
4 spliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Gene diagram · NM_000546.6 · variants mapped to exon structure
TP53 NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 2.25917e-05; MAF= 0.00226%, 9/398376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.97991e-05; MAF= 0.00398%, 9/226136 alleles, homozygotes = 0); grpmax FAF= 2.07e-05.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 1/31390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0023% · 9 / 398,376
      0 hom · FAF 0.0021%
      European (non-Finnish)
      9 / 226,136
      0.004%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.0032% · 1 / 31,390
      0 hom
      African/African American
      1 / 8,708
      0.011%
      + 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC