The variant is very rare in population databases, with gnomAD v2.1 total AF 2.04127e-05 (0.00204%) and grpmax FAF 2.326e-05, which are below the generic PM2 rarity threshold of 0.1%.1 gnomAD v4.1 likewise shows a total AF of 1.44198e-05 (0.00144%) and grpmax FAF 3.005e-05, which remains below the generic PM2 rarity threshold of 0.1% and confirms that the variant is uncommon in the general population.2 SpliceAI predicts minimal splicing effect, with a maximum delta score of 0.03, which is below the splice-impact threshold of 0.2 and supports BP4.3 ClinVar contains a likely benign classification for this variant with single-submitter review status, which is concordant with a benign leaning but is not used as stand-alone classification evidence.4 Because the available data provide one supporting pathogenic criterion for rarity and one supporting benign criterion for computational evidence against splice disruption, NM_006231.4:c.4006-15C>T is classified as a variant of uncertain significance.
Final classification
VUS
PM2BP4
POLE
c.4006-15C>T
p.?
This variant
The variant is very rare in population databases, with gnomAD v2.1 total AF 2.04127e-05 (0.00204%) and grpmax FAF 2.326e-05, which are below the generic PM2 rarity threshold of 0.1%.
Conflicting supporting evidence under generic ACMG/AMP: PM2 is met for rarity and BP4 is met for benign computational splicing evidence.
Classification rationale
PM2
BP4
VUS
POLE c.4006-15C>T
PM2 + BP4
→
VUS
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_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
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
PM2
review
Pathogenic
The variant is rare in population databases: gnomAD v2.1 total AF is 2.04127e-05 (0.00204%) with grpmax FAF 2.326e-05, and gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) with grpmax FAF 3.005e-05; these values are below the generic PM2 rarity threshold of 0.1%.
gnomAD v2.1 AF 2.04127e-05; grpmax FAF 2.326e-05gnomAD v4.1 AF 1.44198e-05; grpmax FAF 3.005e-05
BP4
review
Benign
Computational evidence supports no impact on splicing because the SpliceAI maximum delta score is 0.03, which is below the splice-impact threshold of 0.2.
SpliceAI DS_AG 0.01, DS_AL 0.03, DS_DG 0.01, DS_DL 0.00; max delta 0.03
Assessed · not applied
· 4 not met · 16 not assessed
Pathogenic
PVS1
NM_006231.4:c.4006-15C>T is an intronic variant 15 bases upstream of exon 32, and SpliceAI shows a maximum delta score of 0.03, which is below the splicing concern threshold of 0.2; no evidence in the case file demonstrates a null effect or predicted exon skipping/cryptic splice creation sufficient for PVS1.
PS1
PS1 requires the same amino acid change as an established pathogenic variant, and no such matched protein-altering comparison is relevant for this intronic variant in the available record.
PS2
No de novo data with confirmed maternity and paternity are provided.
PS3
No functional assay demonstrating a damaging effect on POLE splicing or function is provided.
PS4
No case-control enrichment, case series, or prevalence comparison supporting increased occurrence in affected individuals is provided.
PM1
No evidence places this intronic position in a defined mutational hot spot or critical functional domain without benign variation.
PM6
No assumed de novo occurrence data are provided.
PP1
No segregation data are provided.
PP3
Computational evidence does not support a deleterious splicing effect because the SpliceAI maximum delta score is 0.03, which is below the commonly used splice-impact threshold of 0.2.
PP4
No phenotype, tumor spectrum, or family history data specific enough to POLE-associated disease are provided.
PP5
Although ClinVar contains a classification, PP5 is not applied here as stand-alone evidence.
Benign
BA1
Benign stand-alone frequency is not met because gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) and gnomAD v2.1 total AF is 2.04127e-05 (0.00204%), both well below the generic BA1 threshold of 1%.
BS1
Benign strong frequency is not met because gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) and gnomAD v2.1 total AF is 2.04127e-05 (0.00204%), both below the generic BS1 threshold of 0.3%.
BS2
No data demonstrate observation in healthy adult individuals at a level sufficient for BS2.
BS3
No functional assay demonstrating a benign effect is provided.
BS4
No nonsegregation data are provided.
BP2
No phase data with another pathogenic variant are provided.
BP5
No alternate molecular explanation or case-level data are provided to support BP5.
BP6
ClinVar lists this variant as likely benign with single-submitter review status, but BP6 is not used here as stand-alone evidence.
BP7
The intronic position and low SpliceAI score are compatible with a benign splicing interpretation, but the available record does not provide the additional conservation assessment needed to apply BP7 confidently.
N/A · 6
PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.44198e-05; MAF= 0.00144%, 21/1456334 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.98519e-05; MAF= 0.00699%, 6/85896 alleles, homozygotes = 0); grpmax FAF= 3.005e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.04127e-05; MAF= 0.00204%, 5/244946 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.77552e-05; MAF= 0.00878%, 3/34186 alleles, homozygotes = 0); grpmax FAF= 2.326e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014%
· 21 / 1,456,334
0 hom · FAF 0.003%
0 hom · FAF 0.003%
South Asian 6 / 85,896 |
0.007% |
Admixed American 3 / 44,452 |
0.0067% |
Remaining individuals 2 / 60,188 |
0.0033% |
African/African American 1 / 33,410 |
0.003% |
European (non-Finnish) 9 / 1,110,426 |
0.00081% |
+ 4 not observed (European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian)
gnomAD v2.1
0.002%
· 5 / 244,946
0 hom · FAF 0.0023%
0 hom · FAF 0.0023%
Admixed American 3 / 34,186 |
0.0088% |
South Asian 2 / 30,214 |
0.0066% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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