3-12379754-A-T

Variant summary

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

The NM_138711.6(PPARG):c.43A>T(p.Ile15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,036 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).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PPARG
NM_138711.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.99

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=0.034247518).

BP6

Variant 3-12379754-A-T is Benign according to our data. Variant chr3-12379754-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2630467.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000341 (52/152298) while in subpopulation AFR AF= 0.00111 (46/41564). AF 95% confidence interval is 0.000852. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARG	NM_138711.6 linkuse as main transcript	c.43A>T	p.Ile15Phe	missense_variant	3/8	ENST00000651735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARG	ENST00000651735.1 linkuse as main transcript	c.43A>T	p.Ile15Phe	missense_variant	3/8		NM_138711.6	P1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

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:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250984

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00

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:

0.0000212

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000341

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00111

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:

0.00

Alfa

AF:

0.0000496

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

PPARG-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

The PPARG c.133A>T variant is predicted to result in the amino acid substitution p.Ile45Phe. This variant has been found in controls in a cohort study of type 2 diabetes and interpreted as benign; however, obesity status was not noted (Majithia et al. 2014. PubMed ID: 25157153). This variant is reported in 0.092% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-12421253-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.10

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.025

MetaRNN

Benign

0.034

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

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.99

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.53

N;N;N;N;.;.;.;D;N;N;N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.010

D;D;D;D;.;.;.;D;D;D;D;D;D

Sift4G

Benign

0.11

T;D;T;T;.;.;.;T;T;T;T;D;T

Polyphen

0.92, 0.096

.;.;.;.;.;.;.;.;.;.;.;P;B

Vest4

0.64

MVP

0.60

MPC

0.42

ClinPred

0.11

GERP RS

3.2

Varity_R

0.18

gMVP

0.54

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