ENST00000287820.10:c.34C>A

Variant names:

• chr3-12351626-C-A
• rs1801282
• ENST00000287820.10:c.34C>A
• PPARG p.Pro12Thr

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The ENST00000287820.10(PPARG):​c.34C>A​(p.Pro12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PPARG ENST00000287820.10 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.395
• Publications: 0 publications found

Genes affected

PPARG (HGNC:9236): (peroxisome proliferator activated receptor gamma) This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2008]

PPARG Gene-Disease associations (from GenCC):

• PPARG-related familial partial lipodystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• lipodystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1192 (below the threshold of 3.09). Trascript score misZ: 3.0297 (below the threshold of 3.09). GenCC associations: The gene is linked to PPARG-related familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy, lipodystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.090531915).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000287820.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	NM_138711.6	MANE Select	c.-8-28078C>A		intron	N/A	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.34C>A	p.Pro12Thr	missense	Exon 1 of 7	NP_056953.2
	PPARG	NM_001354668.2		c.34C>A	p.Pro12Thr	missense	Exon 1 of 5	NP_001341597.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000287820.10	TSL:1	c.34C>A	p.Pro12Thr	missense	Exon 1 of 7	ENSP00000287820.6	P37231-1
	PPARG	ENST00000651735.1	MANE Select	c.-8-28078C>A		intron	N/A	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000397010.7	TSL:1	c.-8-28078C>A		intron	N/A	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458576 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 725838

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109016

Other (OTH) AF: 0.0000166 AC: 1 AN: 60278

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	PPARG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.091	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.40
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.035	Neutral
Varity_R		0.093
gMVP		0.36
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1801282;

hg19: chr3-12393125;