rs147975759

Variant names:

• chr3-12381449-T-C
• rs147975759
• NM_138711.6:c.348T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_138711.6(PPARG):​c.348T>C​(p.Ala116Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,664 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: PPARG NM_138711.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.25
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-12381449-T-C is Benign according to our data. Variant chr3-12381449-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 342922.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000604 (92/152276) while in subpopulation AMR AF = 0.00249 (38/15286). AF 95% confidence interval is 0.00186. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.348T>C	p.Ala116Ala	synonymous	Exon 4 of 8	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.438T>C	p.Ala146Ala	synonymous	Exon 3 of 7	NP_056953.2
	PPARG	NM_001354666.3		c.348T>C	p.Ala116Ala	synonymous	Exon 4 of 8	NP_001341595.2	E9PFV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.348T>C	p.Ala116Ala	synonymous	Exon 4 of 8	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000287820.10	TSL:1	c.438T>C	p.Ala146Ala	synonymous	Exon 3 of 7	ENSP00000287820.6	P37231-1
	PPARG	ENST00000397010.7	TSL:1	c.348T>C	p.Ala116Ala	synonymous	Exon 4 of 8	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000619 AC: 155 AN: 250598 AF XY: 0.000650

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000374 AC: 546 AN: 1461388 Hom.: 1 Cov.: 31 AF XY: 0.000380 AC XY: 276 AN XY: 726996

African (AFR) AF: 0.000478 AC: 16 AN: 33450

American (AMR) AF: 0.00202 AC: 90 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.000649 AC: 56 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5762

European-Non Finnish (NFE) AF: 0.000217 AC: 241 AN: 1111754

Other (OTH) AF: 0.000977 AC: 59 AN: 60360

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74446

African (AFR) AF: 0.000337 AC: 14 AN: 41558

American (AMR) AF: 0.00249 AC: 38 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68018

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000523 Hom.: 0

Bravo AF: 0.000710

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	INSULIN RESISTANCE, DIGENIC (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Obesity (1)
-	-	1	PPARG-related familial partial lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.7
DANN	Benign	0.43
PhyloP100		-1.2
Mutation Taster		=98/2	polymorphism

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: rs147975759; hg19: chr3-12422948;