Variant classification summary

NM_002691.4:c.2251-23A>G

POLD1 · NP_002682.2:p.? · NM_002691.4

GRCh37: chr19:50916976 A>G · GRCh38: chr19:50413719 A>G

Gene: POLD1 Transcript: NM_002691.4

Final call

Benign

BS1 strong BS2 strong BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.?

gnomAD AF

0.0023156516309417573 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BS1 (strong) is met because the gnomAD v2.1 genome allele frequency is 0.0126578.

2

Benign: BS2 (strong) is met because gnomAD reports 27 v2.1 and 86 v4.1 homozygotes.

3

Benign: BP4 (supporting) is met because SpliceAI maximum delta is 0.002.

Final determination: Generic ACMG/AMP 2015 fallback rules classify a variant as Benign when at least two strong benign criteria are met; BS1 strong and BS2 strong satisfy this rule.

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	N/A	Not applicable: NM_002691.4:c.2251-23A>G is intronic at −23 and is neither a nonsense, frameshift, nor canonical ±1/2 splice variant.	pvs1_generic_framework pvs1_variant_assessment spliceai
PS1	N/A	Not applicable: the intronic variant has protein consequence p.?, so no amino-acid change exists for same-codon comparison.
PS2	Not assessed	Not assessed: no proband genotype, parental testing, confirmed parentage, or documented de novo event is available for this variant.
PS3	Not assessed	Not assessed: no validated RNA, protein, or minigene assay is documented; SpliceAI maximum delta 0.002 is computational, not functional evidence.	spliceai PMID:25741868
PS4	Not assessed	Not assessed: no affected-case series, control comparison, or case-control enrichment metric is available for this exact intronic POLD1 variant.
PM1	N/A	Not applicable: the intronic variant has no protein residue to compare with a critical functional domain, and no POLD1-specific domain table is available.
PM2	Not met	Not met: gnomAD v4.1 overall allele frequency is 0.00231565, exceeding the generic PM2 cutoff of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected proband, second pathogenic allele, or phase result documents this variant in trans for a recessive disorder.
PM4	N/A	Not applicable: the variant has no predicted protein-length change, with protein consequence NP_002682.2:p.?.	pvs1_variant_assessment PMID:25741868
PM5	N/A	Not applicable: protein consequence p.? provides no defined residue for comparison with pathogenic missense variants at the same position.
PM6	Not assessed	Not assessed: no clinical report supports a presumed de novo occurrence without parental testing for this variant.
PP1	Not assessed	Not assessed: no affected relatives, unaffected tested carriers, informative meioses, or genotype-phenotype segregation data are documented.
PP2	N/A	Not applicable: PP2 concerns missense variation, whereas this variant is intronic and has protein consequence p.?.
PP3	Not met	Not met: SpliceAI maximum delta 0.002 is below the >=0.2 PP3 supporting threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical features are provided to evaluate specificity for a POLD1-associated disorder.
PP5	Not met	Not met: ClinVar variation 676636 has zero expert-panel submissions and only exact-variant laboratory classifications of Benign or Likely benign.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 0.0471935 in gnomAD v2.1 AFR_XX, below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Met	Met at strong: gnomAD v2.1 genome allele frequency is 0.0126578, exceeding the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Met	Met at strong: gnomAD v4.1 reports 86 homozygotes, although the all-comers population dataset does not directly verify healthy-adult status.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no validated benign-function assay is documented; SpliceAI maximum delta 0.002 cannot establish normal POLD1 function.	spliceai PMID:25741868
BS4	Not assessed	Not assessed: no informative affected non-carrier or unaffected carrier is documented in a family tested for this variant.
BP1	N/A	Not applicable: BP1 concerns missense variants, but this intronic variant has no defined amino-acid consequence and is reported as p.?.
BP2	Not assessed	Not assessed: no phase-resolved observation establishes this variant in trans or cis with a pathogenic allele under the generic BP2 rule.
BP3	N/A	Not applicable: this is a single-nucleotide intronic substitution, not an in-frame deletion or insertion in a repetitive region.	pvs1_variant_assessment PMID:25741868
BP4	Met	Met at supporting strength: SpliceAI maximum delta 0.002 meets the <=0.1 BP4 supporting threshold.	spliceai
BP5	Not assessed	Not assessed: no patient phenotype or pathogenic variant in another gene is documented to provide an alternative explanation.
BP6	Not met	Not met: ClinVar variation 676636 has zero expert-panel submissions, so its exact-variant Benign and Likely benign laboratory labels do not qualify for BP6.	clinvar
BP7	N/A	Not applicable: the variant is intronic, whereas BP7 applies only to synonymous variants.

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.