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.
TP53
Final classification
VUS
PM2BP4BP7
TP53
c.-29+100dup
p.?
This variant
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).
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
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 applied · 9 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at an extremely low allele frequency in gnomAD v4.1 (total AF=2.26×10⁻⁵, 9/398,376 alleles), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003. The highest subpopulation frequency is in European (non-Finnish) at AF=3.98×10⁻⁵ (9/226,136 alleles), which is below the subpopulation threshold of 0.00004.
gnomAD v4.1 total AF=2.26×10⁻⁵ (9/398376 alleles)European (non-Finnish) AF=3.98×10⁻⁵ (9/226
✓
BP4
supporting
Benign
NM_000546.6:c.-29+100dup is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP PP3/BP4/BP7 flowchart, intronic variants with SpliceAI ≤ 0.1 qualify for BP4_Supporting. SpliceAI max delta score for this variant is 0.00, satisfying this threshold.
SpliceAI max delta score = 0.00below BP4 threshold of ≤0.1 for intronic variants outside ±12. No predicted splicing impact.
✓
BP7
supporting
Benign
NM_000546.6:c.-29+100dup is an intronic variant at position +100 of intron 1, which is beyond the +7 position. Per the TP53 VCEP BP7 rule, intronic variants at or beyond +7 to −21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1) qualify for BP7_Supporting. SpliceAI max delta score is 0.00, satisfying this criterion.
Intronic position +100 (beyond +7)SpliceAI max delta = 0.00BP4 met
Assessed · not applied
· 3 not met · 6 not assessed
Pathogenic
PS2
No de novo observation data are available for this variant.
PS4
No proband or case-control data are available for this variant.
PP1
No co-segregation data are available for this variant.
PP3
The TP53 VCEP PP3 rule for intronic variants (excluding ±1,2) requires SpliceAI ≥ 0.2.
PP4
No phenotype or variant allele fraction (VAF) data are available for this variant.
Benign
BA1
The TP53 VCEP BA1 threshold requires a filtering allele frequency (FAF) ≥ 0.001 (0.1%) in a gnomAD continental subpopulation (excluding founder populations).
BS1
The TP53 VCEP BS1 threshold requires FAF ≥ 0.0003 (0.03%) but < 0.001 in a gnomAD subpopulation with ≥2,000 alleles tested and ≥2 alleles present.
BS2
No data on unaffected elderly females carrying this variant are available.
BS4
No segregation data in affected families are available for this variant.
N/A · 15
PVS1 · PS1 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6
Research & evidence
Population frequency
gnomAD v4.1
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%
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
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
0 hom
Not observed in any ancestry group.
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.
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.
Sources & reference links