rs3856806

Positions:

• chr3-12434058-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_138711.6(PPARG):​c.1341C>T​(p.His447=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,614,040 control chromosomes in the GnomAD database, including 13,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1153 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12668 hom.)
• Consequence: PPARG NM_138711.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.333

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-12434058-C-T is Benign according to our data. Variant chr3-12434058-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.333 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARG	NM_138711.6	c.1341C>T	p.His447=	synonymous_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.1341C>T	p.His447=	synonymous_variant	8/8		NM_138711.6	ENSP00000498313	P1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17378 AN: 152060 Hom.: 1149 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0869

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.0895

GnomAD3 exomes AF: 0.134 AC: 33702 AN: 251322 Hom.: 2568 AF XY: 0.136 AC XY: 18405 AN XY: 135826

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.128 AC: 187677 AN: 1461862 Hom.: 12668 Cov.: 32 AF XY: 0.129 AC XY: 93871 AN XY: 727234

Gnomad4 AFR exome AF: 0.0572

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0740

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.114 AC: 17390 AN: 152178 Hom.: 1153 Cov.: 32 AF XY: 0.116 AC XY: 8636 AN XY: 74384

Gnomad4 AFR AF: 0.0638

Gnomad4 AMR AF: 0.0869

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.0895

Alfa AF: 0.120 Hom.: 2734

Bravo AF: 0.102

Asia WGS AF: 0.133 AC: 463 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2019	This variant is associated with the following publications: (PMID: 18992148, 17141766, 22575725, 21795447, 10851250, 21833536, 9467001) -

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. -

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Glioma susceptibility 1 Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 01, 2000

- -

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
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.1
DANN	Benign	0.53

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: rs3856806; hg19: chr3-12475557; COSMIC: COSV55140736;