chr3-12379739-C-G

Position:

• chr3-12379739-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_138711.6(PPARG):​c.28C>G​(p.Pro10Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPARG NM_138711.6 missense
• Clinical Significance: risk factor no assertion criteria provided O:4
• Conservation: PhyloP100: 4.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2985686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARG	NM_138711.6	c.28C>G	p.Pro10Ala	missense_variant	3/8	ENST00000651735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARG	ENST00000651735.1	c.28C>G	p.Pro10Ala	missense_variant	3/8		NM_138711.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:4

Revision: no assertion criteria provided

Submissions by phenotype

Body mass index, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Obesity, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Intimal medial thickness of internal carotid artery, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Diabetes mellitus, noninsulin-dependent, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T;.;.;.;.;.;.;.;T;T;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;.;.;.;.;.;.;.;D;.;.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.0	.;.;.;.;.;.;.;.;.;.;.;.;L
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N;N;.;.;.;D;N;N;D;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0070	D;D;D;D;.;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;D;.;.;.;T;D;D;T;D;D
Polyphen		0.35, 0.20	.;.;.;.;.;.;.;.;.;.;.;B;B
Vest4		0.67
MutPred		0.26		.;.;.;.;.;.;.;.;.;.;.;.;Loss of glycosylation at T41 (P = 0.048);
MVP		0.54
MPC		0.14
ClinPred		0.74	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.35

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: rs1805192; hg19: chr3-12421238;