NM_006231.4:c.1687-18G>A

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133248926 C>T · GRCh38: chr12:132672340 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 BP4

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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%.

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%.

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.

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.

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 determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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.	spliceai
PS1	N/A	PS1 is not applicable because this variant does not define an amino acid substitution.
PS2	Not assessed	No de novo data were provided.
PS3	Not assessed	No well-established functional assay data were provided for this variant.
PS4	Not assessed	No case-control enrichment or multiple affected observations were provided.
PM1	N/A	PM1 is not applicable because this is not a missense or in-frame coding change localizable to a mutational hot spot or critical protein domain.
PM2	Met	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 gnomad_v2
PM3	N/A	PM3 is not applicable because this criterion is intended for recessive disorders and no trans configuration evidence was provided.
PM4	N/A	PM4 is not applicable because this variant is not an in-frame deletion, insertion, or stop-loss event.
PM5	N/A	PM5 is not applicable because this variant does not encode a missense change.
PM6	Not assessed	No assumed de novo data were provided.
PP1	Not assessed	No segregation data were provided.
PP2	N/A	PP2 is not applicable because this is not a missense variant.
PP3	Not met	Computational evidence does not support a deleterious splice effect because SpliceAI shows a maximum delta score of 0.01.	spliceai
PP4	Not assessed	No phenotype or family history data specific to a POLE-associated syndrome were provided.
PP5	Not met	No reputable-source pathogenic classification was provided for this variant.	clinvar
BA1	Not met	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%.	gnomad_v4
BS1	Not met	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%.	gnomad_v4
BS2	Not assessed	No evidence was provided showing the variant in healthy adults in a context sufficient to satisfy BS2.
BS3	Not assessed	No well-established functional studies demonstrating lack of damaging effect were provided.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation were provided.
BP1	N/A	BP1 is not applicable because this variant is not a missense change.
BP2	Not assessed	No phase data with another pathogenic variant were provided.
BP3	N/A	BP3 is not applicable because this is not an in-frame indel or repeat-region event.
BP4	Met	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.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided.
BP6	Not assessed	ClinVar contains a single Likely benign submission, but the available record does not by itself establish BP6 as a standalone criterion in this review.	clinvar
BP7	Not assessed	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.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.