rs1801282

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000287820.10(PPARG):c.34C>G(p.Pro12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,609,512 control chromosomes in the GnomAD database, including 11,398 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.089 ( 771 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10627 hom. )

Consequence

PPARG
ENST00000287820.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.395

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011972487).

BP6

Variant 3-12351626-C-G is Benign according to our data. Variant chr3-12351626-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 130019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARG	NM_138711.6 linkuse as main transcript	c.-8-28078C>G		intron_variant		ENST00000651735.1	NP_619725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARG	ENST00000651735.1 linkuse as main transcript	c.-8-28078C>G		intron_variant			NM_138711.6	ENSP00000498313	P1

Frequencies

GnomAD3 genomes

AF:

0.0893

AC:

13577

AN:

152022

Hom.:

768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0843

Gnomad ASJ

AF:

0.0577

Gnomad EAS

AF:

0.0406

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.0638

GnomAD3 exomes

AF:

0.110

AC:

27634

AN:

251078

Hom.:

1759

AF XY:

0.111

AC XY:

15096

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.0565

Gnomad EAS exome

AF:

0.0383

Gnomad SAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.165

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.115

AC:

168301

AN:

1457372

Hom.:

10627

Cov.:

AF XY:

0.117

AC XY:

84648

AN XY:

725298

show subpopulations

Gnomad4 AFR exome

AF:

0.0154

Gnomad4 AMR exome

AF:

0.118

Gnomad4 ASJ exome

AF:

0.0562

Gnomad4 EAS exome

AF:

0.0360

Gnomad4 SAS exome

AF:

0.123

Gnomad4 FIN exome

AF:

0.170

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0892

AC:

13574

AN:

152140

Hom.:

771

Cov.:

AF XY:

0.0897

AC XY:

6672

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0212

Gnomad4 AMR

AF:

0.0842

Gnomad4 ASJ

AF:

0.0577

Gnomad4 EAS

AF:

0.0405

Gnomad4 SAS

AF:

0.123

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.126

Gnomad4 OTH

AF:

0.0631

Alfa

AF:

0.105

Hom.:

722

Bravo

AF:

0.0805

TwinsUK

AF:

0.108

AC:

401

ALSPAC

AF:

0.119

AC:

460

ESP6500AA

AF:

0.0261

AC:

115

ESP6500EA

AF:

0.124

AC:

1063

ExAC

AF:

0.110

AC:

13366

Asia WGS

AF:

0.0570

AC:

199

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 26049557, 26025336, 26273662, 25216344, 24319532, 23300871, 22800638, 24141935, 23633103, 28386678, 29632382, 28924543, 24447396, 11289055, 26551672, 23666678, 27398621, 11289057, 9792554, 21155004, 25157153, 22276212, 20591056, 17495181, 20930717, 9806549, 10973253, 10873398, 21833536, 20450366, 22378291, 10851250, 21795447, 20623456, 22575725, 19465486, 20368233, 21508507, 20424228, 12974743, 19178525, 22168210, 17187763, 22958899, 23161442) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Obesity

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Diabetes Mellitus, Noninsulin-Dependent, with Acanthosis Nigricans and Hypertension

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

PPARG-related familial partial lipodystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0012

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.96

P;P;P;P;P;P;P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.050

REVEL

Benign

0.24

Sift

Uncertain

0.015

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.075

MPC

0.12

ClinPred

0.019

GERP RS

2.9

Varity_R

0.075

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over