About POLD1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLD1 c.2718-24A>C, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
This variant is present at a frequency that greatly exceeds the maximum expected for a highly penetrant rare dominant disorder: gnomAD v2.1 allele frequency is 0.458% (358/78,106 alleles) and v4.1 is 0.494% (2,810/568,564 alleles), both above the BS1 threshold of >0.3%. The grpmax filtering allele frequency is 6.53% (v2.1) and 2.04% (v4.1), further supporting that this is a common polymorphism.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no deleterious impact: SpliceAI predicts no significant splicing effect (max delta score = 0.00), with no evidence of cryptic splice site creation or disruption. REVEL and BayesDel are not applicable to this intronic variant but their absence does not contradict the benign assessment.
Recorded classification: Likely benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong benign, BP4 supporting benign; combination = 1 strong benign + 1 supporting benign, which maps to Likely Benign.
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
2,810 / 568,564 alleles
gnomAD v4.1: 2,810 / 568,564 alleles. Recorded AF 0.00494228. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00458351; MAF= 0.45835%, 358/78106 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.0155039; MAF= 1.55039%, 96/6192 alleles, homozygotes = 0); grpmax FAF= 0.0653219.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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
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.
29 criteria with recorded statuses: 2 met · 16 not met · 2 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002691.4:c.2718-24A>C is an intronic variant in POLD1 located 24 bases upstream of exon 21, outside the canonical splice consensus region.
SpliceAI predicts no significant splicing impact (max delta score = 0.00), indicating this variant is unlikely to alter normal splicing (BP4).
The variant is present in gnomAD v2.1 at an allele frequency of 0.458% (358/78,106 alleles) and in v4.1 at 0.494% (2,810/568,564 alleles), far exceeding the maximum credible population frequency for a highly penetrant rare dominant disorder such as polymerase proofreading-associated polyposis (BS1).
The variant is absent from ClinVar with no disease associations or submissions, and no publications were identified that specifically mention this variant.
Based on the generic ACMG/AMP 2015 classification framework (PMID:25741868), the combination of one strong benign criterion (BS1) and one supporting benign criterion (BP4) supports a classification of Likely Benign.
No criteria match.
Met · 2
BS1 StrongThis variant is present at a frequency that greatly exceeds the maximum expected for a highly penetrant rare dominant disorder: gnomAD v2.1 allele frequency is 0.458% (358/78,106 alleles) and v4.1 is 0.494% (2,810/568,564 alleles), both above the BS1 threshold of >0.3%. The grpmax filtering allele frequency is 6.53% (v2.1) and 2.04% (v4.1), further supporting that this is a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.458% (>0.3%)
- grpmax FAF=6.53%
- gnomAD v4.1 AF=0.494% (>0.3%)
- grpmax FAF=2.04%
- 0 homozygotes observed but very high allele counts in population databases.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: SpliceAI predicts no significant splicing effect (max delta score = 0.00), with no evidence of cryptic splice site creation or disruption. REVEL and BayesDel are not applicable to this intronic variant but their absence does not contradict the benign assessment. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- no predicted impact on splicing
- no computational evidence of pathogenicity.
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo occurrence report with confirmed maternity and paternity was identified for this variant in the literature; a de novo event must be directly observed in a published study to apply PS2. Details ▾Hide ▴
Evidence considered
- No publications mention this variant
- absent from ClinVar.
Still missing
- No proband or family data available.
PS3 No well-established in vitro or in vivo functional studies supporting a damaging effect on the gene product were identified for this specific variant. Details ▾Hide ▴
Evidence considered
- No functional assays found for NM_002691.4:c.2718-24A>C in any evidence source.
Still missing
- No functional study data available for this intronic variant.
PS4 No case-control data or enriched observation in affected individuals beyond population frequency is available; the variant is absent from ClinVar with no curated disease associations. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar with zero curated submissions
- gnomAD frequencies are consistent with a benign polymorphism.
Still missing
- No case-control or cohort enrichment data.
Sources
PM1 This intronic variant is not located within a well-established functional domain or mutational hot spot; cancer hotspot analysis confirms no residue-level significance. Details ▾Hide ▴
Evidence considered
- Intronic position c.2718-24 is not within any characterized functional domain
- hotspot analysis negative.
PM2 This variant is present in gnomAD at an allele frequency of 0.458% (v2.1, 358/78,106 alleles) and 0.494% (v4.1, 2,810/568,564 alleles), both well above the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.458%
- gnomAD v4.1 AF=0.494%
- both >0.1% PM2 cutoff.
Sources
PM6 No de novo observation (without confirmation of maternity/paternity) was identified for this variant; a de novo report must be directly read from a published source to apply PM6. Details ▾Hide ▴
Evidence considered
- No publications mention this variant
- absent from ClinVar.
Still missing
- No proband or family data available.
PP1 No cosegregation data in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No family-based cosegregation studies identified.
Still missing
- Family cosegregation data unavailable.
PP3 Multiple lines of computational evidence do not support a deleterious effect: SpliceAI predicts no significant splicing impact (max delta = 0.00); REVEL and BayesDel are not applicable to this intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- no in silico pathogenicity predictions applicable to an intronic variant outside the splice consensus.
Sources
PP5 No reputable source has reported this variant as pathogenic; the variant is absent from ClinVar with zero submissions. Details ▾Hide ▴
BA1 The overall allele frequency in gnomAD is 0.458% (v2.1) and 0.494% (v4.1), both below the BA1 threshold of >1% for a dominant disorder. Although subpopulation frequencies are elevated in the Amish (18.97%, v4.1) and Finnish (1.55%, v2.1), BA1 is assessed using the total population frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF=0.458%
- gnomAD v4.1 total AF=0.494%
- both <1% BA1 cutoff.
Sources
BS2 Although the variant is observed in many heterozygous carriers across gnomAD (358 alleles in v2.1, 2,810 in v4.1), gnomAD includes individuals ascertained through disease studies and does not constitute a confirmed healthy adult control cohort; BS2 requires observation in healthy adults with full expected penetrance. Details ▾Hide ▴
Evidence considered
- High allele counts in gnomAD are suggestive but gnomAD is not a confirmed healthy control cohort.
Still missing
- Confirmed healthy adult control data with phenotype documentation.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on the gene product were identified for this specific variant. Details ▾Hide ▴
Evidence considered
- No functional assays found for NM_002691.4:c.2718-24A>C in any evidence source.
Still missing
- No functional study data available.
BS4 No family cosegregation data demonstrating lack of segregation with disease is available for this variant. Details ▾Hide ▴
Evidence considered
- No family-based studies identified.
Still missing
- Family segregation data unavailable.
BP2 No data available regarding observation in trans with a pathogenic variant for a fully penetrant dominant gene, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase or co-occurrence data available.
Still missing
- Genotype phase data from proband testing required.
BP5 No case has been identified in which this variant is found in a patient with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate-molecular-basis data available.
Still missing
- Proband-level alternate diagnosis data required.
BP6 No reputable source has reported this variant as benign; the variant is absent from ClinVar with zero submissions. Details ▾Hide ▴
Not assessed · 2 · no assessment recorded
PP4 No patient phenotype or family history information is available for this variant; PP4 requires a phenotype highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available.
Still missing
- Clinical phenotype data required.
PS5 No data available regarding observation in trans with a pathogenic variant for a recessive disorder or on the opposite allele for a dominant disorder; cannot be assessed without proband genotyping data. Details ▾Hide ▴
Evidence considered
- No proband-level genotype or phase data available.
Still missing
- Proband genotyping and phase information required.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis intronic variant (c.2718-24A>C) does not fall into the ClinGen PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants); the pvs1_variant_assessment framework confirms variant_bucket='other' and apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
- Variant is intronic at position c.2718-24
- not within ±1
- 2 of any exon-intron junction
- SpliceAI predicts no splicing impact (max delta=0.00).
Sources
PS1 N/APS1 applies only to nucleotide changes that produce the same amino acid change as an established pathogenic variant; this is an intronic variant with no predicted protein consequence. Details ▾Hide ▴
Evidence considered
- Intronic variant does not alter protein coding sequence.
PM3 N/APM3 applies to recessive disorders and requires detection in trans with a pathogenic variant; POLD1-related disease is inherited in an autosomal dominant manner (PPAP), and no phase data is available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants; this is a single nucleotide intronic substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies only to novel missense changes at an amino acid residue where a different pathogenic missense change has been observed; this is an intronic variant with no amino acid consequence (NP_002682.2:p.?). Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid residue to assess for PM5 comparator logic.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism; this is an intronic variant and does not alter the protein coding sequence. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense alteration.
BP1 N/ABP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease; this is an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense alteration.
BP3 N/ABP3 applies to in-frame deletions/insertions in a repetitive region without a known function; this is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) coding variants for which splicing prediction algorithms predict no impact; this is a deep intronic variant (c.2718-24A>C), not a synonymous coding change, and therefore the criterion does not directly apply. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a synonymous coding variant.
Identifiers
- Gene
- POLD1
- Transcript
- NM_002691.4
- Coding (HGVS c.)
- NM_002691.4:c.2718-24A>C
- Protein (HGVS p.)
- NP_002682.2:p.?
- GRCh38
- chr19:50415700 A>C
- GRCh37
- chr19:50918957 A>C
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2,810 / 568,564 alleles
AF 0.00494 · 0 homozygotes · FAF 0.0204
gnomAD v2.1
358 / 78,106 alleles
AF 0.00458 · 0 homozygotes · FAF 0.0653
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.0049 · 2810 / 568,564 alleles · 0 hom · FAF 0.02
| Amish11 / 58 | 0.19 |
| African/African American509 / 23,140 | 0.022 |
| European (Finnish)158 / 14,032 | 0.011 |
| Admixed American164 / 24,242 | 0.0068 |
| Ashkenazi Jewish64 / 11,834 | 0.0054 |
| South Asian195 / 45,812 | 0.0043 |
| European (non-Finnish)1598 / 412,362 | 0.0039 |
| Remaining individuals80 / 22,614 | 0.0035 |
| Middle Eastern5 / 1,790 | 0.0028 |
| East Asian26 / 12,680 | 0.0021 |
gnomAD v2.1
AF 0.0046 · 358 / 78,106 alleles · 0 hom · FAF 0.065
| European (Finnish)96 / 6,192 | 0.016 |
| Admixed American83 / 9,532 | 0.0087 |
| Remaining individuals12 / 2,268 | 0.0053 |
| South Asian57 / 12,620 | 0.0045 |
| African/African American20 / 5,134 | 0.0039 |
| European (non-Finnish)78 / 32,444 | 0.0024 |
| Ashkenazi Jewish10 / 4,938 | 0.002 |
| East Asian2 / 4,978 | 0.0004 |
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00494228; MAF= 0.49423%, 2810/568564 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.189655; MAF= 18.96552%, 11/58 alleles, homozygotes = 0); grpmax FAF= 0.0204173.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00458351; MAF= 0.45835%, 358/78106 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.0155039; MAF= 1.55039%, 96/6192 alleles, homozygotes = 0); grpmax FAF= 0.0653219.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact: SpliceAI predicts no significant splicing effect (max delta score = 0.00), with no evidence of cryptic splice site creation or disruption. REVEL and BayesDel are not applicable to this intronic variant but their absence does not contradict the benign assessment. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- no predicted impact on splicing
- no computational evidence of pathogenicity.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect: SpliceAI predicts no significant splicing impact (max delta = 0.00); REVEL and BayesDel are not applicable to this intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00
- no in silico pathogenicity predictions applicable to an intronic variant outside the splice consensus.
Sources
BP7 N/ABP7 applies to synonymous (silent) coding variants for which splicing prediction algorithms predict no impact; this is a deep intronic variant (c.2718-24A>C), not a synonymous coding change, and therefore the criterion does not directly apply. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a synonymous coding variant.
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
2,810 / 568,564 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
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002691.4%3Ac.2718-24A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-50918957-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-50415700-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002691.4%3Ac.2718…
- OncoKB ↗www.oncokb.org/gene/POLD1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLD1+c.2718-24A%3EC
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= 0.00494228; MAF= 0.49423%, 2810/568564 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.189655; MAF= 18.96552%, 11/58 alleles, homozygotes = 0); grpmax FAF= 0.0204173.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00458351; MAF= 0.45835%, 358/78106 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.0155039; MAF= 1.55039%, 96/6192 alleles, homozygotes = 0); grpmax FAF= 0.0653219.
ClinVar
This variant is absent from ClinVar.
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).