Classification rationale

PM2 BP4 VUS

POLD1 c.203-13C>A

The POLD1 c.203-13C>A (p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and shows 0/1,602,912 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% rarity threshold and supports PM2 at supporting strength.² SpliceAI predicts no significant splice impact for this intronic change, with a maximum delta score of 0.15, which supports BP4 and does not support PP3.³

PM2 + BP4 → VUS

1 evidence.json:results.cosmicevidence.json:results.clinvar

2 evidence.json:results.gnomad.GNOMAD_V2_1evidence.json:results.gnomad.GNOMAD_V4_1

3 evidence.json:results.spliceai

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_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 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 supporting Pathogenic

Population frequency is below the rarity threshold. This variant is absent from gnomAD v2.1 and has 0/1,602,912 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% PM2 threshold.

gnomAD v2.1: absent.gnomAD v4.1: total AC 0, AN 1602912, AF 0.0%; highest subpopulation AC 0, AN 74744, AF 0.0%.

BP4 supporting Benign

Computational splice prediction does not support a deleterious effect. SpliceAI showed a maximum delta score of 0.15, which is below commonly used splice-impact thresholds and is consistent with no significant splice disruption.

SpliceAI max delta score 0.15 with DS_AG 0.14, DS_AL 0.15, DS_DG 0.00, and DS_DL 0.01.

Assessed · not applied · 3 not met · 12 not assessed

Pathogenic

PS1 No evidence was identified showing that this variant results in the same established pathogenic amino acid change as a previously classified variant.

PS2 No confirmed de novo occurrence with verified parentage was identified.

PS3 No well-established functional studies evaluating the effect of this specific variant on RNA splicing or protein function were identified.

PS4 No case-control or enrichment data were identified showing this variant is more common in affected individuals than in controls.

PM6 No assumed de novo occurrence without confirmed parentage was identified.

PP1 No segregation data were identified showing this variant tracks with disease in affected family members.

PP3 Available computational evidence does not support a damaging splicing effect.

PP4 No phenotype or family history information was identified to determine whether the clinical presentation is highly specific for a POLD1-related disorder.

Benign

BA1 Population frequency does not meet the stand-alone benign threshold.

BS1 Population frequency does not support a benign classification.

BS2 No evidence was identified showing this variant in healthy adults in a manner sufficient to argue against pathogenicity.

BS3 No well-established functional studies demonstrating a normal effect of this specific variant were identified.

BS4 No family data were identified showing lack of segregation with disease.

BP2 No allelic data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.

BP5 No alternate molecular explanation for disease was identified for the evaluated individual.

N/A · 11 PVS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1602912 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74744 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,602,912
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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.

COSMIC ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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