TP53 c.-29+131G>T, p.?
NM_000546.6:c.-29+131G>T
Variant of Uncertain Significance (VUS)
NM_000546.6:c.-29+131G>T is classified as a VUS due to the application of PM2_Supporting and BP4_Supporting and BP7_Supporting, with no additional pathogenic or strong benign evidence; key data (functional, segregation, case observations) are lacking, resulting in unresolved significance.
ACMG/AMP Criteria Applied
PM2
BP4
BP7
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.-29+131G>T
Protein Change
?
Location
Exon 1
(Exon 1 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.-29+131G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The TP53 -29+131g>T variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.21
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'Null Variant (nonsense, fs, start codon, splicing +1/2, etc.) in a gene where LOF is a known mechanism.' The evidence for this variant shows: it is a deep intronic variant (c.-29+131G>T) not at canonical splice sites and does not introduce a stop codon. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant.' The evidence for this variant shows: no coding or amino acid change. Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) with points based on family history.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well‐established functional studies show a deleterious effect.' The evidence for this variant shows: no functional assay data available. Therefore, this criterion is not applied due to missing functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Aggregate case points from probands reaching specified thresholds.' The evidence for this variant shows: no case or proband data available. Therefore, this criterion is not applied due to lack of case‐control or proband data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Missense variants within specific hotspot codons or cancerhotspots.org with ≥10 somatic occurrences.' The evidence for this variant shows: it is intronic, not a missense variant. Therefore, this criterion is not applied because it is not a missense change.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting: allele frequency <0.00003 in gnomAD or other large database.' The evidence for this variant shows: absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: TP53 is autosomal dominant and no trans data available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss.' The evidence for this variant shows: no in-frame indel or length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Missense variant at a residue with other pathogenic missense variants.' The evidence for this variant shows: intronic location, no amino acid residue affected. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo without confirmation.' The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Cosegregation observed in affected family members with specified meioses.' The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied due to missing segregation data.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense and missense as common mechanism.' The evidence for this variant shows: intronic, no missense effect. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'SpliceAI ≥0.2 or BayesDel above threshold for missense.' The evidence for this variant shows: SpliceAI score 0.01 (below threshold) and no missense change. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype highly specific for gene.' The evidence for this variant shows: no phenotype information. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source has classified variant as pathogenic.' The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: FAF ≥0.001 in any continental subpopulation.' The evidence for this variant shows: allele frequency = 0. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: FAF ≥0.0003 but <0.001.' The evidence for this variant shows: allele frequency = 0. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Unrelated healthy individuals ≥60 years without cancer.' The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Well‐established functional studies show no deleterious effect.' The evidence for this variant shows: no functional assays available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense in gene where only LOF is disease mechanism.' The evidence for this variant shows: intronic, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with pathogenic variant for dominant disorders.' The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in repetitive regions.' The evidence for this variant shows: no indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Intronic variants outside ±1,2 positions with SpliceAI ≤0.1.' The evidence for this variant shows: SpliceAI maximum score = 0.01 at position +131. Therefore, this criterion is applied at Supporting strength because there is no predicted impact on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source has classified variant as benign.' The evidence for this variant shows: not present in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Intronic variant at or beyond +7 to -21 positions with SpliceAI ≤0.1.' The evidence for this variant shows: position +131 from exon, SpliceAI = 0.01. Therefore, this criterion is applied at Supporting strength because it is a deep intronic variant with no predicted splice impact.