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POLD1c.3068-6C>GUncertain significance
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Variant interpretation report

POLD1 c.3068-6C>G, p.?

NM_002691.4:c.3068-6C>G 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.

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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases. In gnomAD v2.1, it is observed at an allele frequency of 6.45e-6 (1/154,990 alleles) and in gnomAD v4.1 at 2.58e-6 (4/1,549,734 alleles). Both are well below the 0.1% threshold for PM2 in non-VCEP mode. No homozygotes have been observed.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

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
4 / 1,549,734 alleles

gnomAD v4.1: 4 / 1,549,734 alleles. Recorded AF 2.58109e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.45203e-06; MAF= 0.00065%, 1/154990 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 4.0476e-05; MAF= 0.00405%, 1/24706 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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
No matching record reported

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

Context only COSMIC ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 1 met · 19 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002691.4:c.3068-6C>G is an intronic variant in POLD1 located six bases upstream of exon 25. SpliceAI predicts no splicing impact (max delta score = 0.00).

This variant is extremely rare in population databases, observed at an allele frequency of 2.58e-6 in gnomAD v4.1 (4/1,549,734 alleles) and 6.45e-6 in gnomAD v2.1 (1/154,990 alleles), meeting PM2 at supporting strength.

The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (criteria provided, single submitter). No expert panel review is available, and no pathogenic or benign classification has been reached.

No functional studies, segregation data, case-control analyses, or variant-specific publications exist for this variant. The only associated publication (PMID:28492532) is a methodology paper describing the Sherloc classification framework and does not report this variant.

With only one supporting pathogenic criterion (PM2) and no benign criteria met, this variant remains a Variant of Uncertain Significance under the generic ACMG/AMP 2015 classification framework.

Met · 1

PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v2.1, it is observed at an allele frequency of 6.45e-6 (1/154,990 alleles) and in gnomAD v4.1 at 2.58e-6 (4/1,549,734 alleles). Both are well below the 0.1% threshold for PM2 in non-VCEP mode. No homozygotes have been observed. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 6.45e-6 (1/154
  • 990)
  • 0 homozygotes
  • gnomAD v4.1: AF = 2.58e-6 (4/1
  • 549
  • 734)
  • Maximum subpopulation frequency: 4.11e-5 (African/African American
  • gnomAD v4.1)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 19 · evaluated, threshold not reached

PVS1 NM_002691.4:c.3068-6C>G is an intronic variant located six bases upstream of exon 25. It is not a null variant (nonsense, frameshift, or canonical ±1,2 splice site), and SpliceAI predicts no splice impact (max delta score = 0.00). The variant does not meet PVS1 criteria under the ClinGen SVI generic framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Intronic variant at c.3068-6
  • not a canonical ±1
  • 2 splice site
  • SpliceAI max delta score = 0.00
  • no predicted splice alteration
  • Variant bucket classified as 'other' in PVS1 assessment — not eligible for null-variant PVS1
Sources
pvs1_generic_framework ↗spliceai ↗
PS2 No de novo data are available for this variant. The only associated publication (PMID:28492532) is a methodology paper describing the Sherloc classification framework and does not report any patient cases. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 No functional studies have been identified for NM_002691.4:c.3068-6C>G. No variant-specific experimental data exist in the literature or in curated databases (OncoKB, COSMIC). Details ▾Hide ▴
Still missing
  • No functional studies available for this variant
PS4 This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae). No case-control studies, cohort studies, or statistically enriched observations in affected individuals are available. Details ▾Hide ▴
Evidence considered
  • ClinVar: 1 submission
  • VUS
  • single submitter
Still missing
  • No case-control or cohort data available
Sources
clinvar ↗
PM1 This intronic variant (c.3068-6C>G) lies in intron 24, six bases upstream of exon 25. There is no evidence that this intronic position resides within a critical functional domain or established mutational hotspot. SpliceAI predicts no splice impact, and cancerhotspots.org does not list this residue. The variant does not disrupt any characterized functional domain. Details ▾Hide ▴
Evidence considered
  • Intronic position c.3068-6 is not within a known functional domain
  • SpliceAI max delta = 0.00 confirms no predicted impact on the adjacent splice site
  • No hotspot listing at cancerhotspots.org
Sources
spliceai ↗
PM6 No de novo observations have been reported for NM_002691.4:c.3068-6C>G. The only associated publication (PMID:28492532) is a methodology paper and does not report patient cases. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 No segregation data are available for this variant. No family studies have been published. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP3 No in silico tools predict a pathogenic effect. SpliceAI max delta score is 0.00, indicating no predicted splicing alteration. REVEL and BayesDel scores are unavailable as this is an intronic variant with no protein-level consequence. HCI prior is not supported for POLD1. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.00
  • no splice impact predicted
  • REVEL: not applicable (intronic variant)
  • BayesDel: not applicable (intronic variant)
  • HCI prior: gene not supported
Sources
spliceai ↗
PP4 No specific patient phenotype data are available for this variant. The ClinVar submission provides no phenotypic details, and no case reports describing the clinical presentation of carriers have been published. Details ▾Hide ▴
Evidence considered
  • ClinVar submission SCV000829267 provides no phenotype details
Still missing
  • No patient phenotype data available
Sources
clinvar ↗
PP5 ClinVar classifies this variant as Uncertain significance with review status 'criteria provided, single submitter' (1 star). PP5 requires a 3-star expert panel review with a pathogenic or likely pathogenic classification. Neither condition is met. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance
  • Review status: criteria provided
  • single submitter (1 star)
  • No expert panel review available
Sources
clinvar ↗
BA1 The maximum population allele frequency for this variant is 4.11e-5 (0.00411%) in the African/African American population in gnomAD v4.1, well below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 max subpopulation AF = 4.11e-5 (0.00411%)
  • far below 1% BA1 threshold
Sources
gnomad_v4 ↗
BS1 The maximum population allele frequency is 4.11e-5 (0.00411%), well below the 0.3% threshold for BS1 in non-VCEP mode. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 max subpopulation AF = 4.11e-5 (0.00411%)
  • far below 0.3% BS1 threshold
Sources
gnomad_v4 ↗
BS2 No data available on observation of this variant in healthy adults. While no homozygotes are observed in gnomAD, the variant is too rare to draw conclusions about tolerance in the general population. No case-control studies have been published. Details ▾Hide ▴
Still missing
  • No systematic data on observation in healthy adult controls
BS3 No functional studies demonstrating no damaging effect have been performed for this variant. No experimental data (in vitro or in vivo) are available. Details ▾Hide ▴
Still missing
  • No functional studies available
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. No family studies have been published for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No evidence is available demonstrating this variant observed in trans with a known pathogenic variant in POLD1. No phase data exist. Details ▾Hide ▴
Still missing
  • No phase data or observation in trans with a pathogenic variant
BP4 While SpliceAI predicts no splice impact (max delta = 0.00), BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. REVEL and BayesDel scores are unavailable for this intronic variant. A single computational predictor is insufficient to satisfy the 'multiple lines' requirement of BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 suggests no splice alteration
  • REVEL/BayesDel unavailable (intronic)
  • only one line of computational evidence
Sources
spliceai ↗
BP6 ClinVar classifies this variant as Uncertain significance with review status 'criteria provided, single submitter' (1 star). BP6 requires a 3-star expert panel review with a benign or likely benign classification. Neither condition is met. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance
  • Review status: criteria provided
  • single submitter (1 star)
  • No expert panel review available
Sources
clinvar ↗
PS5 PS5 applies to novel missense variants at a position where another pathogenic missense change has been established. This is an intronic variant, not a missense change, and no comparator pathogenic variant exists at this intronic position. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to nucleotide changes at the same position as a known pathogenic variant with a different alteration. This is an intronic variant with no known pathogenic intronic comparator at position c.3068-6. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different amino acid change at the same residue as a known pathogenic missense variant. This intronic variant has no protein consequence (NP_002682.2:p.?) and no residue-level comparator can be established. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This is an intronic substitution, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ABP5 requires observation of the variant in a case with an established alternate molecular basis for disease. No such data exist for this variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies specifically to synonymous (silent) variants with no predicted splice impact. NM_002691.4:c.3068-6C>G is an intronic variant, not a synonymous coding variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.3068-6C>G
Protein (HGVS p.)
NP_002682.2:p.?
GRCh38
chr19:50417039 C>G
GRCh37
chr19:50920296 C>G
ClinVar
577693

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…
gnomAD v4.1 4 / 1,549,734 alleles AF 2.58e-06 · 0 homozygotes · FAF 1.09e-05
gnomAD v2.1 1 / 154,990 alleles AF 6.45e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.6e-06 · 4 / 1,549,734 alleles · 0 hom · FAF 1.1e-05
African/African American3 / 73,006 4.1e-05
Admixed American1 / 50,958 2e-05
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

gnomAD v2.1

AF 6.5e-06 · 1 / 154,990 alleles · 0 hom
Admixed American1 / 24,706 4e-05
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.58109e-06; MAF= 0.00026%, 4/1549734 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.10925e-05; MAF= 0.00411%, 3/73006 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.45203e-06; MAF= 0.00065%, 1/154990 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 4.0476e-05; MAF= 0.00405%, 1/24706 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.230
Pangolin splice gain
0.060

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 No in silico tools predict a pathogenic effect. SpliceAI max delta score is 0.00, indicating no predicted splicing alteration. REVEL and BayesDel scores are unavailable as this is an intronic variant with no protein-level consequence. HCI prior is not supported for POLD1. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.00
  • no splice impact predicted
  • REVEL: not applicable (intronic variant)
  • BayesDel: not applicable (intronic variant)
  • HCI prior: gene not supported
Sources
spliceai ↗
BP4 While SpliceAI predicts no splice impact (max delta = 0.00), BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. REVEL and BayesDel scores are unavailable for this intronic variant. A single computational predictor is insufficient to satisfy the 'multiple lines' requirement of BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 suggests no splice alteration
  • REVEL/BayesDel unavailable (intronic)
  • only one line of computational evidence
Sources
spliceai ↗
BP7 N/ABP7 applies specifically to synonymous (silent) variants with no predicted splice impact. NM_002691.4:c.3068-6C>G is an intronic variant, not a synonymous coding variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 4 / 1,549,734 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Uncertain significance 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

This variant is present in gnomAD v4.1 (AF= 2.58109e-06; MAF= 0.00026%, 4/1549734 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.10925e-05; MAF= 0.00411%, 3/73006 alleles, homozygotes = 0); grpmax FAF= 1.091e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.45203e-06; MAF= 0.00065%, 1/154990 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 4.0476e-05; MAF= 0.00405%, 1/24706 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 577693)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Somatic

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