Variant classification summary

NM_002691.4:c.927C>T

POLD1 · NP_002682.2:p.(Pro309=) · NM_002691.4

GRCh37: chr19:50905955 C>T · GRCh38: chr19:50402698 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Pro309=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

2

Final classification VUS: a single supporting pathogenic criterion (PM2) does not meet the generic ACMG/AMP 2015 pathogenic or benign combination thresholds.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion alone satisfies none of the pathogenic, likely pathogenic, benign, or likely benign combination rules, resulting in VUS.

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: as a synonymous change, no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: synonymous (p.Pro309=), so no altered amino acid exists to compare against a previously pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo evidence (proband/parent genotypes or parental testing) was available.
PS3	Not assessed	Not assessed: no validated functional assay evidence for this variant was available.
PS4	Not assessed	Not assessed: no case-control or affected-case enrichment data for this exact variant were available.
PM1	N/A	Not applicable: synonymous variant, so no altered residue exists to evaluate for a mutational hotspot or critical domain.	generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no data establishing this variant in trans with a pathogenic variant were available.
PM4	N/A	Not applicable: synonymous variant, so no protein length change occurs for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense change.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no presumed de novo observation with parental testing was available.
PP1	Not assessed	Not assessed: no segregation data (informative relatives or meioses) were available.
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties are irrelevant.	generic_acmg_combination_rules
PP3	Not assessed	Not assessed: SpliceAI max delta 0.00 predicts no splice impact, but no verified threshold publication was available to apply it.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype or clinical indication data were available to evaluate specificity.
PP5	Not assessed	Not assessed: the exact variant is absent from ClinVar, so no expert-panel assertion exists.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >5% stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no frequency above a benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no evidence of unaffected adult homozygotes or hemizygotes was available.
BS3	Not assessed	Not assessed: no validated functional assay evidence of a normal (benign) effect was available.
BS4	Not assessed	Not assessed: no non-segregation evidence (unaffected relatives tested) was available.
BP1	N/A	Not applicable: no missense change is present, so the gene's truncating-variant mechanism is irrelevant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of the variant in trans or in cis with a pathogenic variant was available.
BP3	N/A	Not applicable: the variant does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not assessed	Not assessed: SpliceAI max delta 0.00 suggests no splice impact, but no verified threshold publication was available to apply BP4.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no affected individual with an alternative molecular diagnosis explaining the phenotype was found.
BP6	Not assessed	Not assessed: the exact variant is absent from ClinVar, so no benign expert-panel assertion exists.	clinvar
BP7	Not assessed	Not assessed: no nucleotide conservation evidence or gene-specific BP7 specification was available.	spliceai generic_acmg_combination_rules

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.