3-12416887-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_138711.6(PPARG):c.913G>C(p.Val305Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V305I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PPARG
NM_138711.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.92

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 -12 ACMG points.

PP2

Missense variant where missense usually causes diseases, PPARG

BP4

Computational evidence support a benign effect (MetaRNN=0.011836261).

BP6

Variant 3-12416887-G-C is Benign according to our data. Variant chr3-12416887-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436394.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}. Variant chr3-12416887-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00118 (179/152264) while in subpopulation AFR AF= 0.00409 (170/41562). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARG	NM_138711.6 linkuse as main transcript	c.913G>C	p.Val305Leu	missense_variant	7/8	ENST00000651735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARG	ENST00000651735.1 linkuse as main transcript	c.913G>C	p.Val305Leu	missense_variant	7/8		NM_138711.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000223

AC:

AN:

250854

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

176

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00433

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.00118

AC:

179

AN:

152264

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.00136

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 12, 2018

ACMG criteria: BS1 (MAF in gnomAD African 0.4%)= VUS; Variant within Ligand binding domain (PMID:19748282 + PDB) but don't think we can say "without benign variation" here [REVEL 0.288 + PP3/6 predictors + BP4/5 predictors= conflicting evidence, not using] -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 08, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

PPARG-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.16

MutationTaster

Benign

1.0

D;D;N;N;N;N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.62

N;N;N;.;.;.;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.12

T;T;T;.;.;.;T;T;T

Sift4G

Benign

0.34

T;T;T;.;.;.;T;T;T

Polyphen

0.015

.;.;.;.;.;.;.;.;B

Vest4

0.30

MutPred

0.46

.;.;.;.;.;.;.;.;Loss of helix (P = 0.1706);

MVP

0.82

MPC

0.96

ClinPred

0.0094

GERP RS

4.2

Varity_R

0.24

gMVP

0.39

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