NM_015869.4:c.881A>G

PPARG · NP_056953.2:p.(His294Arg) · NM_015869.4

GRCh37: chr3:12458264 A>G · GRCh38: chr3:12416765 A>G

Gene: PPARG Transcript: NM_015869.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

PPARG

Transcript

NM_015869.4

Protein

NP_056953.2:p.(His294Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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).

This variant has not been reported in ClinVar, COSMIC, or the published literature. No functional studies, segregation data, or de novo observations are available.

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	N/A	PVS1 is not applicable to missense variants. NM_015869.4:c.881A>G (p.His294Arg) is a missense substitution and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework
PS1	Not met	PS1 requires a different nucleotide change at the same codon resulting in the identical His294Arg amino acid change that has been established as pathogenic. No such comparator variant was identified in ClinVar or the literature. The codon 294 (CAC) could theoretically change to CGC, CGT, CGA, or CGG to encode arginine, but no other nucleotide substitution producing p.His294Arg was found in any evidence source.	clinvar
PS2	N/A	PS2 requires a confirmed de novo variant with both maternity and paternity confirmed. No de novo data are available for this variant.
PS3	N/A	PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. No variant-specific functional studies were identified. REVEL score is 0.093 and BayesDel score is -0.277, neither supporting a deleterious effect. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	revel bayesdel oncokb
PS4	N/A	PS4 requires statistically significant enrichment of the variant in affected individuals compared to controls. No case-control data are available; the variant has not been observed in any affected or control population.
PS5	N/A	PS5 requires the variant to be found in trans with a pathogenic variant for a recessive disorder. PPARG-associated familial partial lipodystrophy type 3 (FPLD3) follows autosomal dominant inheritance, making trans configuration evidence inapplicable.
PM1	Not met	PM1 requires location in a mutational hot spot or a well-established critical functional domain without benign variation. This variant does not lie in a statistically significant hotspot (Cancer Hotspots: not significant). While codon 294 resides within PPARG, no evidence establishes His294 as a critical functional domain residue with absence of benign variation sufficient to meet PM1 under generic ACMG/AMP interpretation.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 requires detection of the variant in trans with a pathogenic variant for a recessive disorder. PPARG-associated disease (FPLD3) follows autosomal dominant inheritance; no recessive disease association established.
PM4	N/A	PM4 requires a protein-length-changing variant (in-frame deletion/insertion or stop-loss). NM_015869.4:c.881A>G is a missense substitution and does not alter protein length.
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue (His294). No ClinVar entries exist for any variant at codon 294. The automated PM5 candidate search confirmed zero same-residue comparator variants with pathogenic classification.	pm5_candidates clinvar
PM6	N/A	PM6 requires a de novo variant without confirmation of paternity and maternity. No de novo data are available for this variant.
PP1	N/A	PP1 requires co-segregation of the variant with disease in multiple affected family members. No family segregation data are available for this variant.
PP2	Not met	PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While PPARG missense variants are a recognized cause of autosomal dominant FPLD3, the specific missense constraint metrics (Z-score, gnomAD missense observed/expected ratio) needed to satisfy the low-benign-missense-rate component of PP2 under generic ACMG/AMP have not been demonstrated.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. The available in silico predictions do not support pathogenicity: REVEL score is 0.093 (well below the typical pathogenic threshold of 0.5), BayesDel score is -0.277 (predicting a benign effect), and SpliceAI shows a maximum delta score of 0.02 (no predicted splice impact). The computational evidence is inconsistent with a deleterious effect and instead trends toward benign.	revel bayesdel spliceai
PP4	N/A	PP4 requires the patient's phenotype or family history to be highly specific for the disease gene. No patient phenotype or clinical data are available for this variant assessment.
PP5	N/A	PP5 requires a reputable source to have reported the variant as pathogenic. This variant is absent from ClinVar with no submissions from any clinical laboratory.	clinvar
BA1	Not met	BA1 requires an allele frequency greater than 1% in population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, far below the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency greater than 0.3% in population databases. The variant is absent from all available population databases, well below the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	BS2 requires observation of the variant in healthy adults at a frequency inconsistent with disease penetrance for a dominant disorder. The variant has not been observed in any individual (affected or control).
BS3	N/A	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on gene function or splicing. No variant-specific functional studies were identified in any evidence source.
BS4	N/A	BS4 requires lack of segregation of the variant with disease in affected family members. No family segregation data are available.
BP1	N/A	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. PPARG-associated FPLD3 is caused by both missense variants (e.g., p.Arg212Trp in PMID:41751985) and truncating variants (e.g., c.418dup in PMID:39017680). Since missense variants are a known disease mechanism for PPARG, BP1 is not applicable.
BP2	N/A	BP2 requires observation of the variant in trans with a pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such configuration data are available.
BP3	N/A	BP3 requires an in-frame deletion/insertion in a repetitive region without known function. NM_015869.4:c.881A>G is a missense substitution, not an in-frame indel.
BP4	Met	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 bayesdel spliceai
BP5	N/A	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant.
BP6	N/A	BP6 requires a reputable source to classify the variant as benign. The variant is absent from ClinVar and has no classification from any source.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact and no evidence of high evolutionary conservation. NM_015869.4:c.881A>G is a missense variant producing p.His294Arg and is not eligible for BP7.

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