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LYFE SCIENCES
Project: HERA
NM_002691.4:c.2953C>T
p.Arg985Trp  ·  POLD1
ACMG/AMP
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Classification rationale
1

The POLD1 c.2953C>T (p.Arg985Trp) variant has been reported in ClinVar as a variant of uncertain significance by five clinical laboratories.

clinvar ↗
2

This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 1.07182e-05 (2/186598) and gnomAD v4.1 AF 5.15439e-06 (8/1552074), both below the 0.1% PM2 threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

Computational evidence is conflicting: SpliceAI predicts possible splice impact with a max delta score of 0.59, whereas REVEL is low at 0.126 and BayesDel is -0.414351, so PP3 and BP4 are not applied.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 1.07182e-05; MAF= 0.00107%, 2/186598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.86441e-05; MAF= 0.00586%, 1/17052 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 5.15439e-06; MAF= 0.00052%, 8/1552074 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.554e-05; MAF= 0.00355%, 3/84412 alleles, homozygotes = 0); grpmax FAF= 9.44e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLD1, a DNA polymerase, is infrequently altered by mutation in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.59). REVEL score = 0.126. BayesDel score = -0.414351.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR985
Hotspots ↗