Variant classification summary

NM_002691.4:c.203-13C>A

POLD1 · NP_002682.2:p.? · NM_002691.4

GRCh37: chr19:50902615 C>A · GRCh38: chr19:50399358 C>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2_supporting BP4_supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The POLD1 c.203-13C>A (p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

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.

3

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.

Final determination: With one supporting pathogenic criterion and one supporting benign criterion, the ACMG/AMP combination rules do not reach Likely Pathogenic, Likely Benign, Benign, or Pathogenic; therefore the variant is classified as a Variant of Uncertain Significance.

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	This intronic variant is located at c.203-13 and is not a nonsense, frameshift, or canonical +/-1,2 splice-site change. Available generic PVS1 assessment does not support applying PVS1 for this variant type.	pvs1_gene_context.json pvs1_variant_assessment.json
PS1	Not assessed	No evidence was identified showing that this variant results in the same established pathogenic amino acid change as a previously classified variant.	clinvar prefetch.json
PS2	Not assessed	No confirmed de novo occurrence with verified parentage was identified.	literature_pass.json
PS3	Not assessed	No well-established functional studies evaluating the effect of this specific variant on RNA splicing or protein function were identified.	literature_pass.json evidence.json
PS4	Not assessed	No case-control or enrichment data were identified showing this variant is more common in affected individuals than in controls.	clinvar literature_pass.json
PM1	N/A	This variant is intronic and no evidence was identified placing it in a well-established functional domain or mutational hotspot without benign variation.	prefetch.json evidence.json
PM2	Met	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.	evidence.json:results.gnomad.GNOMAD_V2_1 evidence.json:results.gnomad.GNOMAD_V4_1
PM3	N/A	No evidence was identified for this variant occurring in trans with a pathogenic variant in a recessive disease context.	literature_pass.json
PM4	N/A	This variant is an intronic substitution and is not predicted to cause a protein length change from an in-frame deletion, insertion, or stop-loss event.	prefetch.json
PM5	N/A	This criterion applies to novel missense changes at an amino acid residue with another pathogenic missense change, which is not the situation for this intronic variant.	prefetch.json
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified.	literature_pass.json
PP1	Not assessed	No segregation data were identified showing this variant tracks with disease in affected family members.	literature_pass.json
PP2	N/A	This criterion is intended for missense variants in genes where missense variation is a common disease mechanism, which does not apply to this intronic variant.	prefetch.json
PP3	Not met	Available computational evidence does not support a damaging splicing effect. SpliceAI showed a maximum delta score of 0.15, which is below commonly used thresholds for predicted splice disruption.	evidence.json:results.spliceai
PP4	Not assessed	No phenotype or family history information was identified to determine whether the clinical presentation is highly specific for a POLD1-related disorder.	case_summary.json
PP5	N/A	No reputable-source pathogenic assertion without accessible primary evidence was identified, and this criterion is not used when primary evidence can be reviewed directly.	clinvar
BA1	Not met	Population frequency does not meet the stand-alone benign threshold. gnomAD v4.1 shows 0/1,602,912 alleles (AF 0.0%), which is below the 1% BA1 threshold.	evidence.json:results.gnomad.GNOMAD_V4_1
BS1	Not met	Population frequency does not support a benign classification. gnomAD v4.1 shows 0/1,602,912 alleles (AF 0.0%), which is below the 0.3% BS1 threshold.	evidence.json:results.gnomad.GNOMAD_V4_1
BS2	Not assessed	No evidence was identified showing this variant in healthy adults in a manner sufficient to argue against pathogenicity.	evidence.json
BS3	Not assessed	No well-established functional studies demonstrating a normal effect of this specific variant were identified.	literature_pass.json evidence.json
BS4	Not assessed	No family data were identified showing lack of segregation with disease.	literature_pass.json
BP1	N/A	This criterion applies to certain missense variants and is not relevant to this intronic variant.	prefetch.json
BP2	Not assessed	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.	literature_pass.json
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region without known function.	prefetch.json
BP4	Met	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.	evidence.json:results.spliceai
BP5	Not assessed	No alternate molecular explanation for disease was identified for the evaluated individual.	case_summary.json
BP6	N/A	No reputable-source benign assertion without accessible primary evidence was identified, and this criterion is not used when primary evidence can be reviewed directly.	clinvar
BP7	N/A	This criterion is generally reserved for synonymous or more distal intronic variants with no predicted splice impact. This variant is intronic at c.203-13, which is too close to the splice junction for BP7 to be applied.	prefetch.json evidence.json:results.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.