NM_000314.8:c.802-3T>A is an intronic variant at position -3 of the acceptor splice site of PTEN intron 7. It is present at extremely low frequency in gnomAD v4.1 (1/1,585,530 alleles, AF=6.3×10⁻⁷).1 This variant has been classified as Likely Benign by the ClinGen PTEN Variant Curation Expert Panel (ClinVar ID 135912, 3-star expert panel review).2 SpliceAI predicts no significant splicing impact (max delta score = 0.07). Computational tools collectively predict no effect on normal splicing, as noted in one clinical laboratory submission.3 The variant is absent from gnomAD v2.1 and observed only once in gnomAD v4.1, meeting PTEN VCEP PM2_Supporting due to extremely low population frequency.4 BP6 is applied at supporting benign level based on the ClinGen PTEN EP classification of Likely Benign (3-star expert panel review).5 No functional splicing assay, de novo, segregation, or case-control data is available for this variant. The overall evidence profile supports a likely benign interpretation consistent with the expert panel classification.
PTEN
Final classification
VUS
PTEN c.802-3T>A · p.?
PTEN
NM_000314.8:c.802-3T>A is an intronic variant at position -3 of the acceptor splice site of PTEN intron 7. It is present at extremely low frequency in gnomAD v4.1 (1/1,585,530 alleles, AF=6.3×10⁻⁷).
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, BP6 supporting benign; no rule matched the adjudicated criteria.
Classification rationale
PM2
BP6
VUS
PTEN c.802-3T>A
PM2 + BP6
→
VUS
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is present at extremely low frequency in population databases, meeting the PTEN VCEP PM2_Supporting threshold. In gnomAD v4.1, it is observed in 1 of 1,585,530 alleles (AF=6.3×10⁻⁷; 0.000063%), which is well below the VCEP threshold of <0.001% (0.00001). The highest subpopulation frequency is in European (non-Finnish) at 1/1,168,048 alleles (AF=8.6×10⁻⁷; 0.000086%), also below the 0.002% subpopulation threshold. Absent from gnomAD v2.1 and gnomAD-Canada.
gnomAD v4.1: AF=6.3×10⁻⁷ (1/1585530 alleles
✓
BP6
supporting
Benign
Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Likely benign.
ClinVar variation ID 135912: Likely Benignreviewed by expert panel (ClinGen PTEN VCEP3-star)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data is available for this variant.
PS3
No RNA, mini-gene, or other splicing assay data is available for this variant.
PS4
No proband counting, case-control study, or PTEN specificity scoring data is available for this variant.
PM6
No assumed or confirmed de novo observations are reported for this variant in ClinVar or the literature.
PP1
No co-segregation data is available for this variant.
PP3
The PTEN VCEP PP3 rule for splicing variants requires concordance of SpliceAI (score 0.5-1) and VarSeak (Class 4-5) predicting a splicing impact.
PP5
The ClinVar expert panel classification for this variant is Likely Benign (ClinVar variation ID 135912), not Pathogenic or Likely Pathogenic.
Benign
BA1
The PTEN VCEP BA1 threshold requires gnomAD filtering allele frequency >0.056% (0.00056).
BS1
The PTEN VCEP BS1_Strong threshold requires AF 0.0043%-0.056% (0.000043-0.00056) and BS1_Supporting requires AF 0.00043%-0.0043% (0.0000043-0.000043).
BS2
The PTEN VCEP BS2 rule requires observation in the homozygous state in a healthy or PHTS-unaffected individual.
BS3
The PTEN VCEP BS3 rule for intronic variants requires RNA, mini-gene, or other splicing assay demonstrating no splicing impact.
BS4
No segregation data is available for this variant.
BP2
No evidence of this variant occurring in trans with a pathogenic/likely pathogenic PTEN variant or in cis with multiple different pathogenic/likely pathogenic PTEN variants.
BP4
The PTEN VCEP BP4 rule for intronic variants requires concordance of both SpliceAI (scores 0-0.2) and VarSeak (Class 1-2) predicting no splicing impact.
BP5
The PTEN VCEP BP5 rule requires at least two cases where the variant is found in individuals with an alternate molecular basis for disease (highly penetrant other gene/disorder, with no phenotypic overlap with PTEN).
N/A · 9
PVS1 · PS1 · PM1 · PM5 · PP2 · PP4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.30704e-07; MAF= 0.00006%, 1/1585530 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.56129e-07; MAF= 0.00009%, 1/1168048 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.3e-05%
· 1 / 1,585,530
0 hom
0 hom
European (non-Finnish) 1 / 1,168,048 |
8.6e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely Benign by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 135912)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
17576681 ↗
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.
CLINVAR
34012068 ↗
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
35802134 ↗
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR