NM_138711.6:c.-8-24615G>A

Variant names:

• chr3-12355089-G-A
• rs4135247
• NM_138711.6:c.-8-24615G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138711.6(PPARG):​c.-8-24615G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 152,014 control chromosomes in the GnomAD database, including 30,695 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 0.63 (30695 hom., cov: 32)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.476
• Publications: 29 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, Genomics England PanelApp
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARG	NM_138711.6	c.-8-24615G>A		intron_variant	Intron 2 of 7	ENST00000651735.1	NP_619725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARG	ENST00000651735.1	c.-8-24615G>A		intron_variant	Intron 2 of 7		NM_138711.6	ENSP00000498313.1

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95246 AN: 151896 Hom.: 30650 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.601

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

GnomAD4 genome AF: 0.627 AC: 95349 AN: 152014 Hom.: 30695 Cov.: 32 AF XY: 0.624 AC XY: 46341 AN XY: 74284

African (AFR) AF: 0.768 AC: 31865 AN: 41478

American (AMR) AF: 0.606 AC: 9258 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2256 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2388 AN: 5170

South Asian (SAS) AF: 0.408 AC: 1970 AN: 4824

European-Finnish (FIN) AF: 0.609 AC: 6425 AN: 10544

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.576 AC: 39136 AN: 67936

Other (OTH) AF: 0.602 AC: 1272 AN: 2114

Alfa AF: 0.594 Hom.: 45788

Bravo AF: 0.639

Asia WGS AF: 0.484 AC: 1679 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.0
DANN	Benign	0.31
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4135247; hg19: chr3-12396588;