PTEN c.254-3del, p.?
NM_000314.8:c.254-3del
Variant of Uncertain Significance (VUS)
The c.254-3del variant in PTEN is an intronic change at the −3 position with no functional or familial data, absent from population databases, and lacking concordant computational evidence. Only PM2_Supporting applies, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.254-3del
Protein Change
?
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.254-3del
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
Unknown
PP3 Applied
No
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, frameshift, canonical ±1,2 splice sites) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: c.254-3del is at the −3 position, not in the canonical ±1 or ±2 splice site. Therefore, this criterion is not applied because the variant does not meet the canonical splice site requirement.
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 regardless of nucleotide change or different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows: no amino acid change is defined and no known pathogenic variant at this position. Therefore, this criterion is not applied due to lack of matching amino acid change or known pathogenic splicing variant.
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." The evidence for this variant shows: no de novo testing or family history data available. Therefore, this criterion is not applied due to absence of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN 254-3del variant has not been functionally characterized." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at any strength because functional impact has not been experimentally assessed.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared with controls or proband specificity scores." The evidence for this variant shows: no case counts or specificity scores reported. Therefore, this criterion is not applied due to lack of case data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: c.254-3del is intronic and outside defined domains. Therefore, this criterion is not applied because it is not in a hot spot or functional domain.
PM2
PM2 (Supporting) 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 evidence for this variant shows: MAF = 0% in gnomAD and other controls. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population datasets.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: inheritance mode and trans observations are unknown. Therefore, this criterion is not applied due to lack of trans configuration data.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region impacting at least one residue in a catalytic motif." The evidence for this variant shows: it is an intronic deletion with no predicted protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: variant is intronic, not missense. 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." The evidence for this variant shows: no de novo assumption data available. Therefore, this criterion is not applied due to lack of de novo information.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members (≥3-4 meioses)." The evidence for this variant shows: no segregation data 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 with low rate of benign missense variation and where missense is common mechanism." The evidence for this variant shows: it is intronic, not missense. 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: Splicing variants require concordance of SpliceAI and VarSeak." The evidence for this variant shows: only SpliceAI predicts a moderate impact; VarSeak data are not available. Therefore, this criterion is not applied because concordant computational evidence is incomplete.
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." The evidence for this variant shows: no phenotype or family history 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 recently reports variant as pathogenic." The evidence for this variant shows: not reported in ClinVar or similar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency >0.00056 in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Allele frequency from 0.000043 up to 0.00056 in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observed in the homozygous state in a healthy PTEN-unaffected individual." The evidence for this variant shows: no homozygous observations reported. 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 damaging effect on protein or splicing." 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 members of two or more families." 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 variant in a gene where only LOF causes disease." The evidence for this variant shows: intronic change. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no such 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 deletions/insertions in a repetitive region." The evidence for this variant shows: intronic deletion, not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: SpliceAI predicts moderate impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP 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 alternate molecular findings 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 evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "A synonymous or intronic variant at or beyond +7/−21 with no predicted splicing impact." The evidence for this variant shows: position −3 is within the splice region and SpliceAI predicts impact. Therefore, this criterion is not applied.