rs1801282

Positions:

• chr3-12351626-C-G
• chr3-12351626-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (771 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10627 hom.)
• Consequence: PPARG ENST00000287820.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.395

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 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	UniProt
PPARG	NM_138711.6	c.-8-28078C>G		intron_variant		ENST00000651735.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13577 AN: 152022 Hom.: 768 Cov.: 32

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

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.: 31 AF XY: 0.117 AC XY: 84648 AN XY: 725298

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.: 32 AF XY: 0.0897 AC XY: 6672 AN XY: 74386

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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	Invitae	Jan 31, 2024	- -

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

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. -

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.96	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.24
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.075
MPC		0.12
ClinPred		0.019	T
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

Other links and lift over

dbSNP: rs1801282; hg19: chr3-12393125; COSMIC: COSV55140710;