Genetic Variant PPARG:c.-9+32385C>T (chr3-12344838-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001374262.3(PPARG):c.-65C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0892 in 152,140 control chromosomes in the GnomAD database, including 766 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.089 ( 766 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PPARG
NM_001374262.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.155

Publications

49 publications found

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 Gene-Disease associations (from GenCC):

PPARG-related familial partial lipodystrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
lipodystrophy
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Berardinelli-Seip congenital lipodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PPARG links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374262.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPARG	NM_138711.6	MANE Select	c.-9+32385C>T	intron	N/A	NP_619725.3	E9PFV2
PPARG	NM_001374262.3		c.-65C>T	5_prime_UTR	Exon 3 of 8	NP_001361191.2	E9PFX5
PPARG	NM_001354666.3		c.-9+32385C>T	intron	N/A	NP_001341595.2	E9PFV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPARG	ENST00000651735.1	MANE Select	c.-9+32385C>T	intron	N/A	ENSP00000498313.1	E9PFV2
PPARG	ENST00000397010.7	TSL:1	c.-9+32385C>T	intron	N/A	ENSP00000380205.3	E9PFV2
PPARG	ENST00000397015.7	TSL:1	c.-8-34866C>T	intron	N/A	ENSP00000380210.3	E9PFV2

Frequencies

GnomAD3 genomes

AF:

0.0893

AC:

13578

AN:

152022

Hom.:

763

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0841

Gnomad ASJ

AF:

0.0578

Gnomad EAS

AF:

0.0407

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.0633

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0892

AC:

13575

AN:

152140

Hom.:

766

Cov.:

AF XY:

0.0898

AC XY:

6674

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0213

AC:

885

AN:

41536

American (AMR)

AF:

0.0839

AC:

1283

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0578

AC:

200

AN:

3462

East Asian (EAS)

AF:

0.0406

AC:

210

AN:

5174

South Asian (SAS)

AF:

0.124

AC:

596

AN:

4816

European-Finnish (FIN)

AF:

0.156

AC:

1644

AN:

10566

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.126

AC:

8583

AN:

67988

Other (OTH)

AF:

0.0626

AC:

132

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

628

1256

1883

2511

3139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.105

Hom.:

1208

Bravo

AF:

0.0802

Asia WGS

AF:

0.0570

AC:

198

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

8.7

(source)

DANN

Benign

0.77

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over