NM_006231.4:c.1687-18G>A is a noncanonical intronic POLE variant observed in gnomAD v4.1 at 8/1447042 alleles (AF 5.52852e-06; 0.00055%), with the highest frequency in South Asians at 4/85948 alleles (AF 4.65398e-05; 0.00465%), which is below the non-VCEP PM2 threshold of 0.1%.1 Population data are similarly rare in gnomAD v2.1 at 3/251248 alleles (AF 1.19404e-05; 0.00119%), with the highest South Asian frequency at 1/30616 alleles (AF 3.26627e-05; 0.00327%), and these values also remain below the BS1 threshold of 0.3% and BA1 threshold of 1%.2 SpliceAI predicts a maximum delta score of 0.01, which is below the 0.2 threshold commonly used to indicate splice-impact concern and supports a benign computational assessment under BP4 rather than pathogenic computational evidence.3 ClinVar contains a single submitter classification of Likely benign, which is directionally consistent with the splice prediction but is not used here as a standalone ACMG criterion.4 With conflicting supporting evidence from rarity and benign computational data, and without stronger pathogenic or benign evidence, NM_006231.4:c.1687-18G>A is classified as a Variant of Uncertain Significance.
Final classification
VUS
PM2BP4
POLE
c.1687-18G>A
p.?
This variant
NM_006231.4:c.1687-18G>A is a noncanonical intronic POLE variant observed in gnomAD v4.1 at 8/1447042 alleles (AF 5.52852e-06; 0.00055%), with the highest frequency in South Asians at 4/85948 alleles (AF 4.65398e-05; 0.00465%), which is below the non-VCEP PM2 threshold of 0.1%.
generic_acmg_2015_with_non_vcep_frequency_thresholds
Classification rationale
PM2
BP4
VUS
POLE c.1687-18G>A
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 · 18 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 v4.1 total AF is 5.52852e-06 (0.00055%) with highest population AF 4.65398e-05 (0.00465%), and gnomAD v2.1 total AF is 1.19404e-05 (0.00119%) with highest population AF 3.26627e-05 (0.00327%); these values are below the non-VCEP PM2 threshold of 0.1%.
gnomAD v4.1: 8/1447042 alleles, total AF 5.528519559211136e-06, best subpopulation South Asian AF 4.65397682319542e-05.gnomAD v2.1: 3/251248 alleles, total AF 1.1940393555371585e-05, best subpopulation South Asian AF 3.266266004703423e-05.
BP4
review
Benign
SpliceAI predicts a maximum delta score of 0.01, which is below the 0.2 threshold commonly used to flag splice-impact concern, supporting a benign computational assessment.
DS_AG 0.0, DS_AL 0.01, DS_DG 0.01, DS_DL 0.0; max delta score 0.01.
Assessed · not applied
· 5 not met · 13 not assessed
Pathogenic
PVS1
This is a noncanonical intronic variant at c.1687-18, and SpliceAI predicts a maximum delta score of 0.01 rather than a loss-of-function splice effect.
PS2
No de novo data were provided.
PS3
No well-established functional assay data were provided for this variant.
PS4
No case-control enrichment or multiple affected observations were provided.
PM6
No assumed de novo data were provided.
PP1
No segregation data were provided.
PP3
Computational evidence does not support a deleterious splice effect because SpliceAI shows a maximum delta score of 0.01.
PP4
No phenotype or family history data specific to a POLE-associated syndrome were provided.
PP5
No reputable-source pathogenic classification was provided for this variant.
Benign
BA1
The highest observed population frequency is 4.65398e-05 (0.00465%) in gnomAD v4.1 South Asians, which is below the non-VCEP BA1 threshold of 1%.
BS1
The highest observed population frequency is 4.65398e-05 (0.00465%) in gnomAD v4.1 South Asians, which is below the non-VCEP BS1 threshold of 0.3%.
BS2
No evidence was provided showing the variant in healthy adults in a context sufficient to satisfy BS2.
BS3
No well-established functional studies demonstrating lack of damaging effect were provided.
BS4
No segregation data demonstrating lack of cosegregation were provided.
BP2
No phase data with another pathogenic variant were provided.
BP5
No alternate molecular explanation for the phenotype was provided.
BP6
ClinVar contains a single Likely benign submission, but the available record does not by itself establish BP6 as a standalone criterion in this review.
BP7
The variant is intronic and outside the canonical splice site with a low SpliceAI score, but no additional conservation assessment or specification allowing BP7 use in this context was provided.
N/A · 8
PS1 · PM1 · 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= 5.52852e-06; MAF= 0.00055%, 8/1447042 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.65398e-05; MAF= 0.00465%, 4/85948 alleles, homozygotes = 0); grpmax FAF= 1.586e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.19404e-05; MAF= 0.00119%, 3/251248 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00055%
· 8 / 1,447,042
0 hom · FAF 0.0016%
0 hom · FAF 0.0016%
South Asian 4 / 85,948 |
0.0047% |
East Asian 1 / 39,638 |
0.0025% |
Admixed American 1 / 44,706 |
0.0022% |
European (non-Finnish) 2 / 1,098,652 |
0.00018% |
+ 5 not observed (Remaining individuals, European (Finnish), Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 251,248
0 hom
0 hom
South Asian 1 / 30,616 |
0.0033% |
Admixed American 1 / 34,580 |
0.0029% |
European (non-Finnish) 1 / 113,702 |
0.00088% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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