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TP53
Final classification
VUS
TP53 c.375+13G>A · p.?
TP53

NM_000546.6:c.375+13G>A is an intronic variant in TP53 at position +13 of intron 4, outside the canonical splice consensus sequence.

Gene
TP53
Transcript
NM_000546.6
HGVS · transcript:coding
NM_000546.6:c.375+13G>A
Consequence
N/A
GRCh38
chr17:7675981 C>T
GRCh37
chr17:7579299 C>T
Basis ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 point-based framework: PM2 supporting (+1) + BP4 supporting benign (-1) + BP7 supporting benign (-1) = -1 points, which maps to VUS.
ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 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.375+13G>A

NM_000546.6:c.375+13G>A is an intronic variant in TP53 at position +13 of intron 4, outside the canonical splice consensus sequence. This variant is extremely rare in population databases, with an allele frequency of 3.72 x 10^-6 in gnomAD v4.1 (6/1,612,114 alleles), meeting TP53 VCEP PM2_Supporting.1 SpliceAI predicts no splicing impact (max delta = 0.02), meeting TP53 VCEP BP4_Supporting and BP7_Supporting for intronic variants at or beyond +7 with SpliceAI ≤ 0.1.2 This variant has been reported in ClinVar as Likely benign by 5 clinical laboratories (ClinVar ID 379461), though review status is 1-star (criteria provided, single submitter) and no 3-star expert panel classification exists.3 No functional data, segregation analysis, de novo observations, or case-control studies are available for this variant. The variant does not alter a protein-coding residue and is not eligible for PVS1, PS1, PS3, PM1, PM5, or BS3 under the TP53 VCEP framework. Under the TP53 VCEP v2.4 point-based system, applying PM2_Supporting (+1), BP4_Supporting (-1), and BP7_Supporting (-1) yields a total of -1 points. Per the VCEP caveat, when at least 2 benign evidence codes are applied and PM2_Supporting is the only pathogenic code, the classification may be overridden to Likely Benign.4

PM2 + BP4 + BP7 VUS
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
Applied · 3
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
This variant is extremely rare in population databases. gnomAD v4.1 total allele frequency is 3.72 x 10^-6 (6/1,612,114 alleles), well below the TP53 VCEP PM2_Supporting threshold of 0.003%. In the European (non-Finnish) subpopulation, frequency is 5.08 x 10^-6 (6/1,179,994 alleles), below the 0.004% threshold for subpopulations with multiple alleles.
gnomAD v4.1: total AF = 3.72e-06 (6/1612114)
BP4 supporting Benign
SpliceAI predicts no splicing impact (max delta = 0.02). Per the TP53 VCEP v2.4, intronic variants outside +/-1,2 positions with SpliceAI ≤ 0.1 meet BP4_Supporting. Multiple lines of computational evidence suggest this variant does not alter splicing.
SpliceAI max delta = 0.02 ≤ 0.1meets TP53 VCEP BP4_Supporting threshold for intronic variants. No predicted donor/acceptor gain or loss.
BP7 supporting Benign
This is an intronic variant at +13 position (beyond +7 from the exon-intron boundary) with SpliceAI max delta = 0.02, predicting no impact on splicing. Per the TP53 VCEP v2.4, intronic variants at or beyond +7 with SpliceAI ≤ 0.1 meet BP7_Supporting.
Variant position: intron 4+13 from the exon 4 donor site (beyond +7 cutoff). SpliceAI max delta = 0.02 ≤ 0.1. BP4 is also met. No requirement for nucleotide conservation assessment per Walker et al.2023 (PMID: 37352859).
Assessed · not applied
Pathogenic
PS2 No de novo observation has been reported for this variant.
PS4 No case-control data or proband counting is available for this variant.
PP1 No cosegregation data is available for this variant.
PP3 SpliceAI predicts no significant splicing impact (max delta score = 0.02).
PP4 The TP53 VCEP PP4 requires observation of the variant with variant allele fraction (VAF) of 5-35%, suggesting somatic mosaicism in a patient with a phenotype specific for TP53-related disease.
Benign
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 1.83 x 10^-6, far below the TP53 VCEP BA1 threshold of ≥0.001 (0.1%).
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 1.83 x 10^-6, far below the TP53 VCEP BS1 threshold of ≥0.0003 (0.03%).
BS2 The TP53 VCEP BS2 requires ≥2 unrelated females aged ≥60 without cancer from a single source.
BS4 No segregation data is available to assess lack of cosegregation with LFS-associated cancers.
N/A · 16 PVS1 · PS1 · PS3 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BS3 · BP1 · BP2 · BP3 · BP5 · BP6
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= 3.72182e-06; MAF= 0.00037%, 6/1612114 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08477e-06; MAF= 0.00051%, 6/1179994 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.99351e-06; MAF= 0.00040%, 1/250406 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163399; MAF= 0.01634%, 1/6120 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037% · 6 / 1,612,114
0 hom · FAF 0.00018%
European (non-Finnish)
6 / 1,179,994
0.00051%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004% · 1 / 250,406
0 hom
Remaining individuals
1 / 6,120
0.016%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories). (ClinVarID = 379461)
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
20301488 ↗ Li-Fraumeni Syndrome. CLINVAR
23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
26140447 ↗ Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR