TP53 c.-29+121G>T, p.?
NM_000546.6:c.-29+121G>T
Variant of Uncertain Significance (VUS)
This deep intronic TP53 variant is absent from population databases and shows no predicted splice impact. Only PM2_Supporting and BP7_Supporting criteria are met, with no other supportive or conflicting evidence, resulting in a classification of VUS.
ACMG/AMP Criteria Applied
PM2
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+121G>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+121G>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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.37
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, 'Canonical splice variants (±1,2 intronic positions): PVS1 applies to predicted splicing alterations...' The variant c.-29+121G>T is located at +121 relative to the exon, outside the canonical ±1,2 splice sites. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant. This deep intronic variant has no protein change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires a confirmed de novo occurrence (maternity and paternity confirmed). No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-established functional studies showing loss of function in TP53-specific assays. No functional studies have been performed for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case–control or proband count evidence with defined point thresholds. No case data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants in TP53 hotspots (codons 175,245,248,249,273,282) or recurrent somatic hotspots. This intronic variant does not affect a hotspot codon. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, 'PM2 applies at Supporting strength for TP53 if allele frequency <0.00003 in gnomAD.' The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to detected in trans observations in a recessive disorder. TP53 is not recessive and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes such as in-frame indels. This is an intronic variant not affecting coding sequence. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at residues with established pathogenic missense variants. This is noncoding. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to presumed de novo without confirmation. No de novo evidence is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation data across affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation rate. This is an intronic variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to missense or splice region variants with in silico evidence of impact (SpliceAI ≥0.2). SpliceAI predicts no impact (score=0). Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 relates to somatic VAF observations. This is a germline assessment with no somatic data. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies a variant as pathogenic. No such classification exists for this variant. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires FAF ≥0.001 in a continental subpopulation. The variant is absent (FAF=0%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires FAF ≥0.0003 but <0.001. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when ≥8 healthy older females are observed with the variant. No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional evidence of no LOF in TP53 assays. No functional data exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when in cis with a pathogenic variant or in trans for a dominant disorder. No such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a single nucleotide intronic variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies to missense variants with benign in silico scores. This is an intronic variant. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in trans with a pathogenic variant for a dominant disorder. No such data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source classifies variant as benign. No such assertion exists. Therefore, BP6 is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, 'Supporting BP7: an intronic variant at or beyond +7 to -21 positions with SpliceAI ≤0.1 and no predicted splice impact.' c.-29+121G>T is at +121 and SpliceAI=0. Therefore, BP7 is applied at Supporting strength.