3-12318715-T-C

Variant names:

• chr3-12318715-T-C
• rs12636454
• NM_138711.6:c.-9+6262T>C

Variant summary

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

The NM_138711.6(PPARG):​c.-9+6262T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,064 control chromosomes in the GnomAD database, including 5,765 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 0.27 (5765 hom., cov: 32)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970
• Publications: 16 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARG	NM_138711.6	c.-9+6262T>C		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.-9+6262T>C		intron_variant	Intron 2 of 7		NM_138711.6	ENSP00000498313.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41465 AN: 151946 Hom.: 5745 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.273 AC: 41527 AN: 152064 Hom.: 5765 Cov.: 32 AF XY: 0.273 AC XY: 20262 AN XY: 74354

African (AFR) AF: 0.299 AC: 12398 AN: 41458

American (AMR) AF: 0.296 AC: 4521 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 837 AN: 3468

East Asian (EAS) AF: 0.326 AC: 1689 AN: 5178

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4818

European-Finnish (FIN) AF: 0.279 AC: 2944 AN: 10566

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17346 AN: 67988

Other (OTH) AF: 0.242 AC: 511 AN: 2110

Alfa AF: 0.263 Hom.: 10388

Bravo AF: 0.280

Asia WGS AF: 0.239 AC: 827 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.4
DANN	Benign	0.35
PhyloP100		0.097
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12636454; hg19: chr3-12360214;