Genetic Variant NM_138711.6:c.-83+5183C>A (chr3-12294317-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_138711.6(PPARG):c.-83+5183C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 152,034 control chromosomes in the GnomAD database, including 6,343 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 0.28 ( 6343 hom., cov: 32)

Consequence

PPARG
NM_138711.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.215

Publications

14 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=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138711.6. 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.-83+5183C>A	intron	N/A	NP_619725.3	E9PFV2
PPARG	NM_001354666.3		c.-83+6642C>A	intron	N/A	NP_001341595.2	E9PFV2
PPARG	NM_001354667.3		c.-9+5183C>A	intron	N/A	NP_001341596.2	E9PFV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPARG	ENST00000651735.1	MANE Select	c.-83+5183C>A	intron	N/A	ENSP00000498313.1	E9PFV2
PPARG	ENST00000397010.7	TSL:1	c.-83+6642C>A	intron	N/A	ENSP00000380205.3	E9PFV2
PPARG	ENST00000397015.7	TSL:1	c.-9+6297C>A	intron	N/A	ENSP00000380210.3	E9PFV2

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43200

AN:

151916

Hom.:

6335

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.134

Gnomad AMR

AF:

0.340

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.487

Gnomad SAS

AF:

0.272

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.256

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.284

AC:

43233

AN:

152034

Hom.:

6343

Cov.:

AF XY:

0.289

AC XY:

21446

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.287

AC:

11904

AN:

41484

American (AMR)

AF:

0.340

AC:

5198

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

835

AN:

3470

East Asian (EAS)

AF:

0.487

AC:

2512

AN:

5160

South Asian (SAS)

AF:

0.273

AC:

1316

AN:

4824

European-Finnish (FIN)

AF:

0.310

AC:

3266

AN:

10542

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.257

AC:

17467

AN:

67954

Other (OTH)

AF:

0.258

AC:

545

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1582

3165

4747

6330

7912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.210

Hom.:

653

Bravo

AF:

0.289

Asia WGS

AF:

0.381

AC:

1317

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

-0.21

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