NM_002691.4:c.2718-24A>C

POLD1 · NP_002682.2:p.? · NM_002691.4

GRCh37: chr19:50918957 A>C · GRCh38: chr19:50415700 A>C

Gene: POLD1 Transcript: NM_002691.4

Final call

Likely Benign

BS1 strong benign BP4 supporting benign

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.?

gnomAD AF

0.004942275627721769 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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 (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.	pvs1_generic_framework
PS1	N/A	PS1 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.
PS2	Not met	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.
PS3	Not met	No well-established in vitro or in vivo functional studies supporting a damaging effect on the gene product were identified for this specific variant.
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PS5	Not assessed	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.
PM1	Not met	This intronic variant is not located within a well-established functional domain or mutational hot spot; cancer hotspot analysis confirms no residue-level significance.
PM2	Not met	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%.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.?).
PM6	Not met	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.
PP1	Not met	No cosegregation data in affected family members is available for this variant.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not assessed	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.
PP5	Not met	No reputable source has reported this variant as pathogenic; the variant is absent from ClinVar with zero submissions.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on the gene product were identified for this specific variant.
BS4	Not met	No family cosegregation data demonstrating lack of segregation with disease is available for this variant.
BP1	N/A	BP1 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.
BP2	Not met	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.
BP3	N/A	BP3 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.
BP4	Met	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.	spliceai
BP5	Not met	No case has been identified in which this variant is found in a patient with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign; the variant is absent from ClinVar with zero submissions.	clinvar
BP7	N/A	BP7 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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants; this is a single nucleotide intronic substitution.

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