rs121909244

Positions:

• chr3-12434111-C-A
• chr3-12434111-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_138711.6(PPARG):​c.1394C>A​(p.Pro465Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPARG NM_138711.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPARG. . Gene score misZ 2.1192 (greater than the threshold 3.09). Trascript score misZ 3.0978 (greater than threshold 3.09). GenCC has associacion of gene with PPARG-related familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARG	NM_138711.6	c.1394C>A	p.Pro465Gln	missense_variant	8/8	ENST00000651735.1	NP_619725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARG	ENST00000651735.1	c.1394C>A	p.Pro465Gln	missense_variant	8/8		NM_138711.6	ENSP00000498313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;.;.;.;.;.;T;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	1.0	.;.;.;.;.;.;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D;D;.;.;.;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;.;.;.;D;D;D
Sift4G	Uncertain	0.023	D;D;D;.;.;.;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;.;D
Vest4		0.80
MutPred		0.74		.;.;.;.;.;.;.;.;Gain of helix (P = 0.0854);
MVP		0.85
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.86
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909244; hg19: chr3-12475610;