An RNA study has shown that NM_000314.8:c.253+5G>A causes exon 4 skipping, resulting in the predicted frameshift transcript consequence p.(Ala72Thrfs*5).1 Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame in biologically relevant transcript NM_000314.8 and lies 5′ to p.D375 (c.1121) meets PVS1 at very strong strength; exon 4 skipping to p.(Ala72Thrfs*5) is consistent with this rule.2 The variant is absent from gnomAD v2.1 and is observed at 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of 0.001% overall and 0.002% within any subpopulation and supports PM2_Supporting.3 With PVS1 and PM2_Supporting under the PTEN VCEP framework, NM_000314.8:c.253+5G>A is classified as likely pathogenic.4
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.253+5G>A
p.?
This variant
An RNA study has shown that NM_000314.8:c.253+5G>A causes exon 4 skipping, resulting in the predicted frameshift transcript consequence p.(Ala72Thrfs*5).
ACMG/AMP classification using ClinGen PTEN VCEP specifications v3.2.0
Classification rationale
PVS1PM2
Likely Pathogenic
PTEN c.253+5G>A
PVS1 + PM2
→
Likely Pathogenic
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
Very Strong
review
Pathogenic
PMID:28677221 reports that NM_000314.8:c.253+5G>A causes exon 4 skipping with predicted protein consequence p.(Ala72Thrfs*5). Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame and is predicted to undergo nonsense-mediated decay in biologically relevant transcript NM_000314.8, and that occurs 5' to p.D375 (c.1121), meets PVS1.
RNA study: exon 4 skippingPredicted frameshift: p.(Ala72Thrfs*5)PTEN PVS1 decision tree threshold at p.D375/c.1121
PM2
Supporting
review
Pathogenic
The variant is absent from gnomAD v2.1 and has 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of <0.001% overall and <0.002% within any subpopulation.
gnomAD v2.1 absentgnomAD v4.1 total AF 0.0gnomAD v4.1 AFR AF 0.0
Assessed · not applied
· 8 not met · 12 not assessed
Pathogenic
PS1
No same-nucleotide pathogenic splice comparator with equal or greater predicted impact was documented in the reviewed workspace materials.
PS2
No confirmed de novo data were provided.
PS3
An RNA study documents abnormal splicing, but this evidence was used to support PVS1 via the PTEN splice/null decision framework rather than being double-counted separately as PS3.
PS4
The reviewed materials did not provide PTEN phenotype specificity scoring or a case-control enrichment dataset sufficient for PS4.
PM1
This is an intronic splice-region variant, not a missense change within PTEN catalytic motif residues 90-94, 123-130, or 166-168.
PM4
This variant does not create an in-frame protein length change or stop-loss event.
PM5
This is not a missense variant at a residue with a different established pathogenic missense change.
PM6
No assumed de novo evidence was provided.
PP1
No segregation data were provided.
PP2
PP2 is a missense-specific rule and does not apply to this intronic splice-region variant.
PP3
SpliceAI shows a maximum delta score of 0.81, consistent with possible splice impact, but the PTEN VCEP rule for splicing variants requires concordance between SpliceAI and VarSeak, and no VarSeak result was available in the reviewed materials.
Benign
BA1
The gnomAD v4.1 allele frequency is 0.0, which is well below the PTEN BA1 threshold of >0.056%.
BS1
The gnomAD v4.1 allele frequency is 0.0, which is below both the PTEN BS1 supporting range of 0.00043%-0.0043% and the strong range of 0.0043%-0.056%.
BS2
No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were provided.
BS3
No functional study demonstrating no damaging effect on splicing or PTEN function was provided.
BS4
No lack-of-segregation evidence was provided.
BP2
No trans, cis, or phase-unknown observations with pathogenic PTEN variants were provided.
BP4
SpliceAI predicts possible splice impact with a maximum delta score of 0.81, which is above the PTEN benign SpliceAI range of 0-0.2 required for BP4, and no concordant benign VarSeak result was provided.
BP5
No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was provided.
BP7
The variant is at +5, which is inside the PTEN BP7 positional requirement of at or beyond +7/-21, and SpliceAI predicts splice impact rather than no impact.
N/A · 6
PM3 · PP4 · PP5 · BP1 · BP3 · BP6
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1448024 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/33128 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,448,024
0 hom
0 hom
Not observed in any ancestry group.
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Middle Eastern, European (non-Finnish), South Asian, Ashkenazi Jewish, East Asian, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.81).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV64300202, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Characterization of cryptic splicing in germline PTEN intronic variants in Cowde
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
Very Strong
Sources & reference links