3-12335845-A-C

Variant names:

• chr3-12335845-A-C
• rs4518111
• NM_138711.6:c.-9+23392A>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+23392A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 151,926 control chromosomes in the GnomAD database, including 33,016 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 0.65 (33016 hom., cov: 31)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.26
• Publications: 5 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	NM_138711.6	MANE Select	c.-9+23392A>C		intron	N/A	NP_619725.3	E9PFV2
	PPARG	NM_001354666.3		c.-9+23392A>C		intron	N/A	NP_001341595.2	E9PFV2
	PPARG	NM_001354667.3		c.-8-43859A>C		intron	N/A	NP_001341596.2	E9PFV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.-9+23392A>C		intron	N/A	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000397010.7	TSL:1	c.-9+23392A>C		intron	N/A	ENSP00000380205.3	E9PFV2
	PPARG	ENST00000397015.7	TSL:1	c.-8-43859A>C		intron	N/A	ENSP00000380210.3	E9PFV2

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98190 AN: 151810 Hom.: 32966 Cov.: 31

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.616

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

GnomAD4 genome AF: 0.647 AC: 98299 AN: 151926 Hom.: 33016 Cov.: 31 AF XY: 0.643 AC XY: 47757 AN XY: 74228

African (AFR) AF: 0.831 AC: 34452 AN: 41434

American (AMR) AF: 0.616 AC: 9400 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2264 AN: 3470

East Asian (EAS) AF: 0.478 AC: 2472 AN: 5176

South Asian (SAS) AF: 0.408 AC: 1960 AN: 4808

European-Finnish (FIN) AF: 0.607 AC: 6388 AN: 10522

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.578 AC: 39277 AN: 67936

Other (OTH) AF: 0.617 AC: 1300 AN: 2108

Alfa AF: 0.604 Hom.: 5629

Bravo AF: 0.663

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.37
PhyloP100		-3.3
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: rs4518111; hg19: chr3-12377344;