About PPARG
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPARG c.338C>T, p.(Pro113Leu)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
NM_015869.4:c.338C>T is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present at an allele frequency of 1.24×10⁻⁶ (0.00012%, 2/1,613,144 alleles) in gnomAD v4.1 with no homozygotes. This frequency is well below the 0.1% threshold for PM2.
PP3Supporting
PP3 · supporting
REVEL in silico predictor assigns a score of 0.74, which is above the commonly accepted threshold for deleterious prediction (>0.5). BayesDel score of 0.293 is borderline. SpliceAI predicts no splicing impact (max delta=0.00). Taken together, the REVEL score provides a single line of computational evidence supporting a deleterious effect.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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, PP3 supporting; combination = 2 supporting, 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
2 / 1,613,144 alleles
gnomAD v4.1: 2 / 1,613,144 alleles. Recorded AF 1.23981e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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 · 19 not met · 2 not assessed · 6 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.338C>T (p.Pro113Leu) in PPARG is a missense variant absent from ClinVar and present at an extremely low allele frequency of 1.24×10⁻⁶ (2/1,613,144 alleles, 0 homozygotes) in gnomAD v4.1, meeting PM2 at supporting strength (well below 0.1% threshold).
REVEL in silico prediction yields a score of 0.74, exceeding the 0.5 threshold for a deleterious call, meeting PP3 at supporting strength. SpliceAI predicts no splicing impact (max delta score 0.00) and BayesDel (0.293) is borderline.
No functional studies, de novo reports, segregation data, or disease-specific cohort data were identified for this variant. PVS1 is not applicable as this is a missense variant (ClinGen SVI PVS1 framework, PMC6185798). All remaining assessed pathogenic and benign criteria were not met.
With only PM2 (supporting) and PP3 (supporting) met, the evidence is insufficient to reach a Likely Pathogenic or Likely Benign classification under generic ACMG/AMP 2015 combination rules (PMID:25741868). This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_015869.4:c.338C>T is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present at an allele frequency of 1.24×10⁻⁶ (0.00012%, 2/1,613,144 alleles) in gnomAD v4.1 with no homozygotes. This frequency is well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=1.24×10⁻⁶ (2/1
- 613
- 144 alleles
- 0 homozygotes)
- highest subpopulation AF=1.34×10⁻⁵ in African/African American
- gnomAD-Canada v1.0: absent
Sources
PP3 SupportingREVEL in silico predictor assigns a score of 0.74, which is above the commonly accepted threshold for deleterious prediction (>0.5). BayesDel score of 0.293 is borderline. SpliceAI predicts no splicing impact (max delta=0.00). Taken together, the REVEL score provides a single line of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.74 (deleterious
- above 0.5 threshold)
- BayesDel score: 0.293 (borderline
- near 0.3 threshold)
- SpliceAI max delta: 0.00 (no predicted splicing impact)
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No prior report of the same amino acid change (p.Pro113Leu) as a pathogenic variant exists in ClinVar or the literature; this variant is absent from all ClinVar records. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no established pathogenic variant exists at this amino acid position with the same change
Sources
PS2 No de novo occurrence data are available for this variant in any database or published literature. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar
- literature_pass
- or any evidence source
Still missing
- De novo status cannot be assessed without parental genotype data
Sources
PS4 No case-control or cohort data are available to assess whether the prevalence of this variant is significantly increased in affected individuals; the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no disease-specific cohorts reported
- gnomAD v4.1 allele count of 2 in 1
- 613
- 144 alleles does not constitute affected-individual evidence
Still missing
- No affected-individual cohort data available
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. Domain-level assessment for a critical functional domain was not performed due to lack of domain annotation in the evidence packet. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not statistically significant
- exact_variant_listed=no
Still missing
- Functional domain annotation for PPARG residue 113 not available
- manual review of PPARG protein domains could identify whether this residue falls within the DNA-binding domain or AF-1 domain
PM6 No assumed or confirmed de novo occurrence has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or any other evidence source
Still missing
- No de novo data available
Sources
PP1 No cosegregation data are available for this variant; no family studies have been reported. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data available in any evidence source
Still missing
- No segregation data available
PP2 PPARG missense constraint metrics are not available in the evidence packet (HCI prior score not available for PPARG). Without evidence of a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior probability not available for PPARG (gene_not_supported)
- no missense constraint data
Still missing
- Missense constraint metrics (e.g.
- gnomAD Z-score
- missense depletion) not available
- manual review of PPARG missense constraint could inform PP2 applicability
PP4 No patient phenotype or family history data were provided for this case; the specificity of the patient's presentation cannot be assessed. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available in the case record
Still missing
- Patient phenotype information not provided in this case
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no prior classification from any submitter
Sources
BA1 The population allele frequency of 1.24×10⁻⁶ (0.00012%) in gnomAD v4.1 is far below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=1.24×10⁻⁶ (0.00012%)
- well below 1% BA1 threshold
- gnomAD v2.1: absent
Sources
BS1 The population allele frequency of 1.24×10⁻⁶ (0.00012%) in gnomAD v4.1 is far below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=1.24×10⁻⁶ (0.00012%)
- well below 0.3% BS1 threshold
- gnomAD v2.1: absent
Sources
BS2 Although 2 alleles are observed in gnomAD v4.1, the phenotype of those individuals is unknown. gnomAD population data alone, without confirmation of healthy adult status in the context of a highly penetrant early-onset disorder, is insufficient to meet BS2. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 2/1
- 613
- 144 alleles
- no phenotype data available for carriers
Still missing
- Phenotype of gnomAD carriers unknown
- cannot confirm healthy adult status
Sources
BS4 No segregation data are available to assess lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No family or segregation studies available
Still missing
- No segregation data available
BP1 PPARG is known to harbor disease-causing missense variants (e.g., familial partial lipodystrophy type 3 is caused by PPARG missense mutations such as p.Arg212Trp). BP1 applies only when truncating variants are the primary disease mechanism, which is not the case for PPARG. Details ▾Hide ▴
Evidence considered
- PPARG missense variants (e.g.
- R212W) are reported as pathogenic for FPLD3
- both truncating and missense mechanisms are associated with disease
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a pathogenic variant has been reported for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans phase data available
Still missing
- No phase or trans configuration data available
BP4 REVEL in silico predictor assigns a score of 0.74, which predicts a deleterious effect. Computational evidence is therefore mixed (REVEL predicts damaging, SpliceAI predicts no splicing impact) and does not provide multiple lines of evidence suggesting no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.74 (deleterious prediction — contradicts BP4)
- SpliceAI max delta: 0.00 (no splicing impact)
- Computational evidence is conflicting
- not uniformly benign
Sources
BP5 No data are available indicating this variant was observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No alternate molecular diagnosis data available
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
PS5 No same-residue different amino acid change (PM5-style comparator) has been established as pathogenic in ClinVar or the literature. PM5 candidate harvesting found no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned 0 same-residue candidates
- no ClinVar pathogenic variant at residue 113
Sources
pm5_candidatesclinvar ↗
Not assessed · 2 · no assessment recorded
PS3 No well-established in vitro or in vivo functional studies were identified for NM_015869.4:c.338C>T (p.Pro113Leu). OncoKB assigns 'Unknown Oncogenic Effect' and provides no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies available
Still missing
- No functional data exist for this specific variant
- experimental functional studies would be required to assess PS3
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for this variant. OncoKB assigns 'Unknown Oncogenic Effect' with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies identified
- OncoKB classification: Unknown Oncogenic Effect
Still missing
- No functional studies exist for this variant
- experimental data would be required to assess BS3
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_015869.4:c.338C>T is a missense variant (p.Pro113Leu); it does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant p.Pro113Leu
- variant_bucket=other
- apply_generic_pvs1_framework=false per pvs1_variant_assessment
Sources
PM3 N/ANo evidence for a recessive disease mechanism or detection in trans with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a substitution, not a protein-length-altering in-frame deletion or insertion. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to confirm classic same-residue PM5 semantics; PM5 candidate harvesting found no eligible pathogenic comparator variants at residue 113. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned 0 same-residue candidates
- eligible_for_classic_pm5_search=false
Sources
pm5_candidates
BP3 N/AVariant is a substitution, not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_015869.4:c.338C>T is a missense variant (p.Pro113Leu), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splicing impact and low nucleotide conservation. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (c.338C>T
- p.Pro113Leu)
- BP7 is restricted to synonymous variants
Identifiers
- Gene
- PPARG
- Transcript
- NM_015869.4
- Coding (HGVS c.)
- NM_015869.4:c.338C>T
- Protein (HGVS p.)
- NP_056953.2:p.(Pro113Leu)
- GRCh38
- chr3:12381349 C>T
- GRCh37
- chr3:12422848 C>T
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
2 / 1,613,144 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,144 alleles · 0 hom
| African/African American1 / 74,862 | 1.3e-05 |
| European (non-Finnish)1 / 1,179,658 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23981e-06; MAF= 0.00012%, 2/1613144 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33579e-05; MAF= 0.00134%, 1/74862 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.740
- BayesDel
- 0.293
How the predictions were used
PP3 SupportingREVEL in silico predictor assigns a score of 0.74, which is above the commonly accepted threshold for deleterious prediction (>0.5). BayesDel score of 0.293 is borderline. SpliceAI predicts no splicing impact (max delta=0.00). Taken together, the REVEL score provides a single line of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.74 (deleterious
- above 0.5 threshold)
- BayesDel score: 0.293 (borderline
- near 0.3 threshold)
- SpliceAI max delta: 0.00 (no predicted splicing impact)
Sources
BP4 REVEL in silico predictor assigns a score of 0.74, which predicts a deleterious effect. Computational evidence is therefore mixed (REVEL predicts damaging, SpliceAI predicts no splicing impact) and does not provide multiple lines of evidence suggesting no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.74 (deleterious prediction — contradicts BP4)
- SpliceAI max delta: 0.00 (no splicing impact)
- Computational evidence is conflicting
- not uniformly benign
Sources
BP7 N/ANM_015869.4:c.338C>T is a missense variant (p.Pro113Leu), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splicing impact and low nucleotide conservation. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (c.338C>T
- p.Pro113Leu)
- BP7 is restricted to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.74. BayesDel score = 0.293355.
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
2 / 1,613,144 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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.338C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-12422848-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-12381349-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-12381349-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015869.4%3Ac.338C…
- OncoKB ↗www.oncokb.org/gene/PPARG/P113L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PPARG+c.338C%3ET
- 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
This variant is present in gnomAD v4.1 (AF= 1.23981e-06; MAF= 0.00012%, 2/1613144 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33579e-05; MAF= 0.00134%, 1/74862 alleles, homozygotes = 0).
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 = 0.00). REVEL score = 0.74. BayesDel score = 0.293355.
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.