PTEN c.-533G>T, p.?
NM_000314.8:c.-533G>T
Population Frequency
0.00652%
Low Frequency
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.-533G>T
Protein Change
?
Location
Exon 1
(Exon 1 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Global Frequency
0.00652%
Rare
Highest in Population
Remaining individuals
0.188%
Common
Global: 0.00652%
Remaining individuals: 0.188%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 30668
Alt: 2
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00652%, 2/30668 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.188%, 2/1066 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications
0 publications
Clinical Statement
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 Studies
Summary
The PTEN -533g>T variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.35
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific." The evidence for this variant shows it is a non‐coding upstream variant (c.-533G>T) that does not introduce a null effect as defined by the decision tree. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no amino acid change (non‐coding). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN pre-processing, the finding for PS3 is: "The PTEN -533g>T variant has not been functionally characterized, and its biological significance remains unknown." Therefore, this criterion is not applied due to lack of functional evidence.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 (Strong) is: "Probands with specificity score 4-15.5 or prevalence significantly increased in cases vs. controls." No case or proband data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)." The variant lies in the 5′ untranslated region, outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population." The observed allele frequency is 0.00652% (0.0000652), which exceeds the threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant in a recessive gene." PTEN is an autosomal dominant gene and no trans data are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The variant is non‐coding and does not affect protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The variant is non‐coding. 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, but without confirmation of paternity and maternity, in proband with the disease and no family history." No de novo or family data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members (3–4 meioses)." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense is a common mechanism." The variant is non‐coding. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product." In silico tools (CADD=2.35, SpliceAI=0.02) predict no deleterious effect. 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 or family history is highly specific for a disease with a single genetic etiology." No phenotypic or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The variant is 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 gnomAD Filtering allele frequency >0.00056 (0.056%)." The allele frequency is 0.00652% (0.0000652), below the threshold. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The observed allele frequency is 0.00652% (0.0000652), which falls between 0.0043% and 0.056%. Therefore, this criterion is applied at Strong strength.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in the homozygous state in a healthy or PHTS‐unaffected individual." No homozygous observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." No functional splicing or protein assays are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members of two or more families." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The variant is non‐coding. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant." No such observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The variant is a single nucleotide change in the 5′ UTR, not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product." In silico tools (CADD=2.35, SpliceAI=0.02) predict no impact on splicing or function. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease." No alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The variant is not reported in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 with no splicing impact." The variant is in the 5′ UTR exon and not an intronic silent variant. Therefore, this criterion is not applied.