Classification rationale

PM2 BP4 VUS

POLD1 c.3218+4T>C unknown · exon 26i

PM2 supporting: gnomAD v4.1 total allele frequency is 6.31e-06 (10/1,584,146 alleles, zero homozygotes) and the variant is absent from gnomAD v2.1. BP4 supporting: SpliceAI maximum delta 0.025 is below the 0.1 threshold, so no splice-altering effect is predicted for this intronic donor +4 change. VUS: one supporting pathogenic criterion plus one supporting benign criterion satisfies no ACMG/AMP 2015 combination rule.

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_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

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 supporting review Pathogenic

Met (supporting): gnomAD v4.1 all-comers AF 6.31e-06 (10/1,584,146 alleles, 0 homozygotes) and absent from v2.1, about 16-fold below the 0.0001 PM2 threshold.

gnomAD v4.1 all-comers totals for chr19-50417273-T-C: AC 10 / AN 1,584,146, AF 6.312549474606508e-06, total homozygotes 0; exome 9/1,431,988 (AF 6.284968868454205e-06, hom 0); genome 1/152,158 (AF 6.572115826969334e-06, hom 0); grpmax FAF 0.00010566; exome grpmax FAF 0.00010209; genome grpmax FAF null.gnomAD v4.1 ancestry data: East Asian AF 0.0002042112906153567 (9/44,072 alleles, 0 homozygotes; EAS_XX 6/22,576; EAS_XY 3/21,496) is the only ancestry with observations; NFE 1/1,167,734 (AF 8.563594106191992e-07, hom 0); 0 alleles in AFR (AN 74,386), SAS (AN 88,898), AMR (AN 58,276), FIN (AN 53,284), ASJ (AN 29,154), MID (AN 5,972), AMI (AN 912) and remaining (AN 61,458); best_subpop = eas.gnomAD v2.1 all-comers query (GRCh37 19-50920530-T-C): search_status 'absent', found = false; the variant is not present in this older all-comers dataset.

gnomad_v4 ↗gnomad_v2 ↗clinvar ↗

BP4 supporting Benign

Met at supporting: SpliceAI max delta 0.025 is at or below the 0.1 splice-impact BP4 threshold.

SpliceAI Lookup result for NM_002691.4:c.3218+4T>C (hg37): max delta score 0.025, DS_DL 0.025, DS_AG 0.002, DS_AL 0.002, DS_DG 0.000; Pangolin SG 0.01 / SL -0.014; scrape status result_found, screenshot captured at screenshots/spliceai.png.Threshold applied verbatim: SpliceAI max delta <= 0.1 = BP4 supporting (Jaganathan et al. 2019, Cell; PMID:30661751); 0.025 is below the cutoff, so BP4 is met at supporting strength.Path selection: because the variant is intronic/splice-region, only the SpliceAI path was used for BP4; the absent REVEL score (found = false) was not substituted, and the same SpliceAI value was not also counted toward PP3, which is separately not met.

spliceai ↗

Assessed · not applied · 12 not met · 6 not assessed

Pathogenic

PVS1 Not met: c.3218+4T>C lies outside the canonical +/-1,2 donor site and SpliceAI max delta 0.025 predicts no aberrant splicing.

PS2 Not assessed: no proband, parental testing, or pedigree data exists, so a confirmed de novo occurrence cannot be evaluated.

PS3 Not met: no functional assay of c.3218+4T>C exists - neither ClinVar submitter nor any retrieved full text reports a splice or protein-function study.

PS4 Not met: no case-control or cohort enrichment data exists for this variant, and no numeric PS4 threshold is available to compare against.

PM4 Not met: this intronic substitution is not an in-frame indel or stop-loss, and SpliceAI 0.025 predicts no length-altering exon skipping.

PM6 Not assessed: with no proband or parental data, neither confirmed nor assumed de novo status can be established for this variant.

PP1 Not assessed: no pedigree, affected relatives, or genotype data, so PP1 co-segregation and meioses cannot be counted.

PP3 Not met: SpliceAI max delta 0.025 falls below the 0.2 supporting threshold for PP3.

PP4 Not assessed: no proband phenotype or family history is recorded anywhere in this case, so phenotype specificity for POLD1 disease cannot be judged.

PP5 Not met: the only ClinVar submissions for this exact variant are two clinical-laboratory Uncertain significance calls with zero expert-panel submissions.

Benign

BA1 Not met: gnomAD v4.1 all-comers AF 6.31e-06 (10/1,584,146 alleles), roughly four orders of magnitude below the 0.05 BA1 threshold.

BS1 Not met: gnomAD v4.1 AF 6.31e-06 versus the 0.01 BS1 threshold, roughly 1,500-fold below even using the highest-ancestry estimate.

BS2 Not met: zero homozygotes in gnomAD v4.1 (10/1,584,146 alleles) and POLD1 disease is adult-onset, incompletely penetrant cancer predisposition, so BS2's premise fails.

BS3 Not met: no functional study of c.3218+4T>C reports normal splicing or protein function; SpliceAI 0.025 is computational, not assay, evidence.

BS4 Not assessed: no family genotype data exists, so non-segregation cannot be demonstrated in this variant's relatives.

BP2 Not met: no phase data exist, so c.3218+4T>C was never observed in cis or in trans with a pathogenic POLD1 variant.

BP5 Not assessed: the case has no proband molecular or clinical data, so no alternate molecular basis for disease can be evaluated for BP5.

BP6 Not met: no expert-panel Benign/Likely benign classification exists for this exact variant, whose ClinVar entries are both Uncertain significance.

N/A · 8 PS1 · PM1 · PM3 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.31255e-06; MAF= 0.00063%, 10/1584146 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000204211; MAF= 0.02042%, 9/44072 alleles, homozygotes = 0); grpmax FAF= 0.00010566.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00063% · 10 / 1,584,146
0 hom · FAF 0.011%

East Asian 9 / 44,072	0.02%
European (non-Finnish) 1 / 1,167,734	8.6e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 647102)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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 ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Rule & framework references · cited for criterion definitions, not variant evidence

17576681 ↗ Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

9536098 ↗ Statistical features of human exons and their flanking regions.

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

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