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).1 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.2 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.3 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.4
POLD1
Final classification
VUS
POLD1 c.3068-6C>G · p.?
POLD1
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).
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.
Classification rationale
PM2
VUS
POLD1 c.3068-6C>G
PM2
→
VUS
Gene diagram
· NM_002691.4 · variants mapped to exon structure
POLD1
NM_002691.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 18 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF = 6.45e-6 (1/154990)0 homozygotes
Assessed · not applied
Pathogenic
PVS1
NM_002691.4:c.3068-6C>G is an intronic variant located six bases upstream of exon 25.
PS2
No de novo data are available for this variant.
PS3
No functional studies have been identified for NM_002691.4:c.3068-6C>G.
PS4
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae).
PM1
This intronic variant (c.3068-6C>G) lies in intron 24, six bases upstream of exon 25.
PM6
No de novo observations have been reported for NM_002691.4:c.3068-6C>G.
PP1
No segregation data are available for this variant.
PP3
No in silico tools predict a pathogenic effect.
PP4
No specific patient phenotype data are available for this variant.
PP5
ClinVar classifies this variant as Uncertain significance with review status 'criteria provided, single submitter' (1 star).
Benign
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.
BS1
The maximum population allele frequency is 4.11e-5 (0.00411%), well below the 0.3% threshold for BS1 in non-VCEP mode.
BS2
No data available on observation of this variant in healthy adults.
BS3
No functional studies demonstrating no damaging effect have been performed for this variant.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP2
No evidence is available demonstrating this variant observed in trans with a known pathogenic variant in POLD1.
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.
BP6
ClinVar classifies this variant as Uncertain significance with review status 'criteria provided, single submitter' (1 star).
N/A · 6
PS1 · PM5 · PP2 · BP1 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00026%
· 4 / 1,549,734
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
African/African American 3 / 73,006 |
0.0041% |
Admixed American 1 / 50,958 |
0.002% |
+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.00065%
· 1 / 154,990
0 hom
0 hom
Admixed American 1 / 24,706 |
0.004% |
+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links