NM_015869.4:c.881A>G (p.His294Arg) in PPARG is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.1 Multiple lines of computational evidence (REVEL 0.093, BayesDel -0.277, SpliceAI max delta 0.02) consistently predict a benign effect on the gene product.2 One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this evidence profile is insufficient to classify the variant as pathogenic, likely pathogenic, benign, or likely benign. The variant is therefore classified as a Variant of Uncertain Significance (VUS).3 This variant has not been reported in ClinVar, COSMIC, or the published literature. No functional studies, segregation data, or de novo observations are available.4
PPARG
Final classification
VUS
PPARG c.881A>G · p.His294Arg
PPARG
NM_015869.4:c.881A>G (p.His294Arg) in PPARG is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
PPARG c.881A>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
3
generic_acmg_combination_rules
Gene diagram
· NM_015869.4 · variants mapped to exon structure
PPARG
NM_015869.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 6 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting level under generic ACMG/AMP guidelines. This absence across large, diverse control populations is consistent with a rare variant of potential clinical significance.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
BP4 is met because multiple lines of computational evidence suggest no impact on the gene product. The REVEL score is 0.093 (well below the pathogenic threshold of 0.5), the BayesDel score is -0.277 (predicting a benign effect), and SpliceAI predicts no significant splice impact (max delta score = 0.02). These concordant benign predictions from multiple algorithm classes satisfy BP4 at supporting benign level.
REVEL=0.093 predicts benign.BayesDel=-0.277 predicts benign.SpliceAI max delta=0.02 predicts no splice impact.
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon resulting in the identical His294Arg amino acid change that has been established as pathogenic.
PM1
PM1 requires location in a mutational hot spot or a well-established critical functional domain without benign variation.
PP2
PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect.
Benign
BA1
BA1 requires an allele frequency greater than 1% in population databases.
BS1
BS1 requires an allele frequency greater than 0.3% in population databases.
N/A · 20
PVS1 · PS2 · PS3 · PS4 · PM3 · PM4 · PM5 · PM6 · PP1 · PP4 · PP5 · BS2 · BS3 · BS4 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.093. BayesDel score = -0.277125.
Functional
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. PPARG, a nuclear receptor, is known to behave as an oncoprotein when fused with with PAX8 in thyroid cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links