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

POLD1 · NP_002682.2:p.? · NM_002691.4

GRCh37: chr19:50920296 C>G · GRCh38: chr19:50417039 C>G

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.?

gnomAD AF

2.5810881093142434e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as 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	Not met	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).	pvs1_generic_framework spliceai
PS1	N/A	PS1 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.
PS2	Not met	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.
PS3	Not met	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).
PS4	Not met	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.	clinvar
PS5	Not met	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.
PM1	Not met	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.	spliceai
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.
PM6	Not met	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.
PP1	Not met	No segregation data are available for this variant. No family studies have been published.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant.
PP3	Not met	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.	spliceai
PP4	Not met	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.	clinvar
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	The maximum population allele frequency is 4.11e-5 (0.00411%), well below the 0.3% threshold for BS1 in non-VCEP mode.	gnomad_v4
BS2	Not met	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.
BS3	Not met	No functional studies demonstrating no damaging effect have been performed for this variant. No experimental data (in vitro or in vivo) are available.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. No family studies have been published for this variant.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This is an intronic substitution, not a missense variant.
BP2	Not met	No evidence is available demonstrating this variant observed in trans with a known pathogenic variant in POLD1. No phase data exist.
BP4	Not met	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.	spliceai
BP5	N/A	BP5 requires observation of the variant in a case with an established alternate molecular basis for disease. No such data exist for this variant.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

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.