POLD1c.203-13C>AUncertain significance

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Variant interpretation report

POLD1 c.203-13C>A, p.?

NM_002691.4:c.203-13C>A NP_002682.2:p.? View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About POLD1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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.
BP4 (supporting): 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.

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.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

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.

Recorded classification: Uncertain significance

Generic ACMG/AMP 2015 final classification combination rules were used because no explicit official or custom gene-specific final-classification framework was available.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

0 / 1,602,912 alleles

gnomAD v4.1: 0 / 1,602,912 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 12 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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

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.

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.

Met · 2

PM2 SupportingPopulation 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. Details ▾Hide ▴

Rule

PM2_supporting applied for AF < 0.1% under generic population rarity fallback.

Evidence considered

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

Sources

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

BP4 SupportingComputational 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. Details ▾Hide ▴

Rule

BP4_supporting applied based on computational evidence suggesting no significant splice impact.

Evidence considered

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

Sources

evidence.json:results.spliceai

Not met · 3 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴

Rule

PP3 not applied because in silico splicing prediction does not indicate significant splice impact.

Evidence considered

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

Sources

evidence.json:results.spliceai

BA1 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. Details ▾Hide ▴

Rule

BA1 requires AF > 1.0%.

Evidence considered

gnomAD v4.1 total AF 0.0%.

Sources

evidence.json:results.gnomad.GNOMAD_V4_1

BS1 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. Details ▾Hide ▴

Rule

BS1 requires AF > 0.3%.

Evidence considered

gnomAD v4.1 total AF 0.0%; highest subpopulation AF 0.0%.

Sources

evidence.json:results.gnomad.GNOMAD_V4_1

Not assessed · 12 · no assessment recorded

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

Evidence considered

Protein consequence is unresolved as p.?.
ClinVar search found no record for this variant.

Still missing

No matching pathogenic variant with the same amino acid consequence was identified.

Sources

clinvar ↗prefetch.json

PS2 No confirmed de novo occurrence with verified parentage was identified. Details ▾Hide ▴

Evidence considered

No publications or case-level de novo data were identified.

Still missing

No parental testing or de novo data were available.

Sources

literature_pass.json

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

Evidence considered

No PMID-linked functional studies were retrieved for this variant.

Still missing

No variant-specific functional assay data were available.

Sources

literature_pass.jsonevidence.json

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

Evidence considered

ClinVar contained no record and no publications were retrieved.

Still missing

No affected-case series or case-control data were available.

Sources

clinvar ↗literature_pass.json

PM6 No assumed de novo occurrence without confirmed parentage was identified. Details ▾Hide ▴

Evidence considered

No case reports were retrieved.

Still missing

No de novo data were available.

Sources

literature_pass.json

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

Evidence considered

No relevant publications were retrieved.

Still missing

No pedigree or segregation data were available.

Sources

literature_pass.json

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

Evidence considered

The available materials did not include phenotype-specific clinical information.

Still missing

No patient phenotype data were available.

Sources

case_summary.json

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

Evidence considered

Population databases show no observed alleles.

Still missing

No healthy carrier data were available.

Sources

evidence.json

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

Evidence considered

No variant-specific functional publications were retrieved.

Still missing

No benign functional assay data were available.

Sources

literature_pass.jsonevidence.json

BS4 No family data were identified showing lack of segregation with disease. Details ▾Hide ▴

Evidence considered

No family-based reports were retrieved.

Still missing

No segregation studies were available.

Sources

literature_pass.json

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. Details ▾Hide ▴

Evidence considered

No case-level allelic observations were retrieved.

Still missing

No phase data were available.

Sources

literature_pass.json

BP5 No alternate molecular explanation for disease was identified for the evaluated individual. Details ▾Hide ▴

Evidence considered

No patient-level alternate diagnosis data were provided.

Still missing

No comprehensive phenotype-genotype context was available.

Sources

case_summary.json

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis 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. Details ▾Hide ▴

Rule

Generic PVS1 fallback from PMC6185798 applies only when the variant falls into an eligible loss-of-function bucket; this variant does not.

Evidence considered

POLD1 is considered eligible for generic PVS1 fallback at the gene level, but NM_002691.4:c.203-13C>A is outside the default null-variant buckets and canonical splice consensus positions.
pvs1_variant_assessment states apply_generic_pvs1_framework=false and canonical_splice_consensus=false.

Sources

pvs1_gene_context.jsonpvs1_variant_assessment.jsonPMC6185798

PM1 N/AThis variant is intronic and no evidence was identified placing it in a well-established functional domain or mutational hotspot without benign variation. Details ▾Hide ▴

Evidence considered

The variant is c.203-13C>A with no protein residue assignment.

Sources

prefetch.jsonevidence.json

PM3 N/ANo evidence was identified for this variant occurring in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴

Evidence considered

No case-level allelic data were identified.

Sources

literature_pass.json

PM4 N/AThis 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. Details ▾Hide ▴

Evidence considered

Variant type is intronic substitution with unresolved protein consequence.

Sources

prefetch.json

PM5 N/AThis 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. Details ▾Hide ▴

Evidence considered

Protein consequence is p.? and the variant is intronic.

Sources

prefetch.json

PP2 N/AThis criterion is intended for missense variants in genes where missense variation is a common disease mechanism, which does not apply to this intronic variant. Details ▾Hide ▴

Evidence considered

Variant is intronic, not missense.

Sources

prefetch.json

PP5 N/ANo reputable-source pathogenic assertion without accessible primary evidence was identified, and this criterion is not used when primary evidence can be reviewed directly. Details ▾Hide ▴

Evidence considered

ClinVar contained no record for this variant.

Sources

clinvar ↗

BP1 N/AThis criterion applies to certain missense variants and is not relevant to this intronic variant. Details ▾Hide ▴

Evidence considered

Variant is intronic, not missense.

Sources

prefetch.json

BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region without known function. Details ▾Hide ▴

Evidence considered

Variant is an intronic single-nucleotide substitution.

Sources

prefetch.json

BP6 N/ANo reputable-source benign assertion without accessible primary evidence was identified, and this criterion is not used when primary evidence can be reviewed directly. Details ▾Hide ▴

Evidence considered

ClinVar contained no record for this variant.

Sources

clinvar ↗

BP7 N/AThis 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. Details ▾Hide ▴

Evidence considered

Variant position is c.203-13 and SpliceAI max delta score is 0.15.

Sources

prefetch.jsonevidence.json:results.spliceai

Identifiers

Gene: POLD1
Transcript: NM_002691.4
Coding (HGVS c.): NM_002691.4:c.203-13C>A
Protein (HGVS p.): NP_002682.2:p.?
GRCh38: chr19:50399358 C>A
GRCh37: chr19:50902615 C>A

Gene diagram

Every interpreted variant in POLD1, mapped onto the exon structure of NM_002691.4. Select a row to find it on the plot.

POLD1NM_002691.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in POLD1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 0 / 1,602,912 alleles AF 0 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,602,912 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

BP4_supporting applied based on computational evidence suggesting no significant splice impact.

Evidence considered

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

Sources

evidence.json:results.spliceai

Rule

PP3 not applied because in silico splicing prediction does not indicate significant splice impact.

Evidence considered

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

Sources

evidence.json:results.spliceai

Evidence considered

Variant position is c.203-13 and SpliceAI max delta score is 0.15.

Sources

prefetch.jsonevidence.json:results.spliceai

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,602,912 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

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

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).