About PPARG
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPARG c.881A>G, p.(His294Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 6 not met · 0 not assessed · 21 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 2
PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
BP4 SupportingBP4 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.093 predicts benign.
- BayesDel=-0.277 predicts benign.
- SpliceAI max delta=0.02 predicts no splice impact.
Sources
Not met · 6 · evaluated, threshold not reached
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. 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. Details ▾Hide ▴
Evidence considered
- No pathogenic same-amino-acid comparator variant at codon 294 identified in ClinVar or literature.
Still missing
- Exhaustive search for alternate nucleotide changes at codon 294 producing His294Arg not performed beyond ClinVar and literature sources.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots analysis: position not statistically significant. No domain-level constraint data for codon 294.
Still missing
- No PPARG-specific domain constraint analysis for codon 294.
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. 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. Details ▾Hide ▴
Evidence considered
- PPARG missense variants are recognized in FPLD3
- but gene-level missense constraint metrics not established.
Still missing
- gnomAD missense Z-score or observed/expected ratio for PPARG not evaluated.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.093 (below pathogenic threshold).
- BayesDel=-0.277 (predicts benign).
- SpliceAI max delta=0.02 (no splice impact).
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- allele frequency = 0.
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- allele frequency = 0.
Sources
Not applicable · 21· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 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. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- ClinGen SVI PVS1 framework (PMC6185798) applies only to null variants.
Sources
PS2 N/APS2 requires a confirmed de novo variant with both maternity and paternity confirmed. No de novo data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
PS3 N/APS3 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. Details ▾Hide ▴
Evidence considered
- No functional studies identified. REVEL=0.093
- BayesDel=-0.277
- OncoKB=Unknown Oncogenic Effect.
Still missing
- No experimental functional data available for this variant.
Sources
PS4 N/APS4 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. Details ▾Hide ▴
Still missing
- No affected individuals have been reported with this variant.
PM3 N/APM3 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. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 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. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 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. Details ▾Hide ▴
Evidence considered
- No ClinVar entries for any missense variant at codon 294. PM5 candidate collection returned zero candidates.
Sources
pm5_candidatesclinvar ↗
PM6 N/APM6 requires a de novo variant without confirmation of paternity and maternity. No de novo data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/APP1 requires co-segregation of the variant with disease in multiple affected family members. No family segregation data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP4 N/APP4 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. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 requires a reputable source to have reported the variant as pathogenic. This variant is absent from ClinVar with no submissions from any clinical laboratory. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available.
Sources
BS2 N/ABS2 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). Details ▾Hide ▴
No further detail was recorded.
BS3 N/ABS3 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. Details ▾Hide ▴
Still missing
- No experimental functional data available for this variant.
BS4 N/ABS4 requires lack of segregation of the variant with disease in affected family members. No family segregation data are available. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
- PPARG disease mechanism includes both missense and truncating variants
- BP1 not applicable.
BP2 N/ABP2 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. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 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. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 requires a reputable source to classify the variant as benign. The variant is absent from ClinVar and has no classification from any source. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification available from any reputable source.
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.His294Arg)
- not synonymous.
PS5 N/APS5 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. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PPARG
- Transcript
- NM_015869.4
- Coding (HGVS c.)
- NM_015869.4:c.881A>G
- Protein (HGVS p.)
- NP_056953.2:p.(His294Arg)
- GRCh38
- chr3:12416765 A>G
- GRCh37
- chr3:12458264 A>G
Gene diagram
Every interpreted variant in PPARG, mapped onto the exon structure of NM_015869.4. Select a row to find it on the plot.
PPARGNM_015869.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PPARG
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.093
- BayesDel
- -0.277
How the predictions were used
BP4 SupportingBP4 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.093 predicts benign.
- BayesDel=-0.277 predicts benign.
- SpliceAI max delta=0.02 predicts no splice impact.
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.093 (below pathogenic threshold).
- BayesDel=-0.277 (predicts benign).
- SpliceAI max delta=0.02 (no splice impact).
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.His294Arg)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.093. BayesDel score = -0.277125.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_015869.4%3Ac.881A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-12458264-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-12416765-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-12416765-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015869.4%3Ac.881A…
- OncoKB ↗www.oncokb.org/gene/PPARG/H294R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PPARG+c.881A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.