3-12351626-C-G

Variant names:

• chr3-12351626-C-G
• rs1801282
• ENST00000287820.10:c.34C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_015869.5(PPARG):​c.34C>G​(p.Pro12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,609,512 control chromosomes in the GnomAD database, including 11,398 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.089 (771 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10627 hom.)
• Consequence: PPARG NM_015869.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.395
• Publications: 1987 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), G2P, Genomics England PanelApp, Orphanet, Ambry Genetics
• 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1192 (below the threshold of 3.09). Trascript score misZ: 3.0297 (below the threshold of 3.09). GenCC associations: The gene is linked to PPARG-related familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011972487).
• BP6: Variant 3-12351626-C-G is Benign according to our data. Variant chr3-12351626-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015869.5. 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.-8-28078C>G		intron	N/A	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.34C>G	p.Pro12Ala	missense	Exon 1 of 7	NP_056953.2
	PPARG	NM_001354668.2		c.34C>G	p.Pro12Ala	missense	Exon 1 of 5	NP_001341597.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000287820.10	TSL:1	c.34C>G	p.Pro12Ala	missense	Exon 1 of 7	ENSP00000287820.6	P37231-1
	PPARG	ENST00000651735.1	MANE Select	c.-8-28078C>G		intron	N/A	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000397010.7	TSL:1	c.-8-28078C>G		intron	N/A	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13577 AN: 152022 Hom.: 768 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.0638

GnomAD2 exomes AF: 0.110 AC: 27634 AN: 251078 AF XY: 0.111

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0565

Gnomad EAS exome AF: 0.0383

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.115 AC: 168301 AN: 1457372 Hom.: 10627 Cov.: 31 AF XY: 0.117 AC XY: 84648 AN XY: 725298

African (AFR) AF: 0.0154 AC: 514 AN: 33424

American (AMR) AF: 0.118 AC: 5268 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 1467 AN: 26122

East Asian (EAS) AF: 0.0360 AC: 1427 AN: 39672

South Asian (SAS) AF: 0.123 AC: 10585 AN: 86168

European-Finnish (FIN) AF: 0.170 AC: 9051 AN: 53378

Middle Eastern (MID) AF: 0.0626 AC: 361 AN: 5764

European-Non Finnish (NFE) AF: 0.121 AC: 133539 AN: 1107902

Other (OTH) AF: 0.101 AC: 6089 AN: 60226

GnomAD4 genome AF: 0.0892 AC: 13574 AN: 152140 Hom.: 771 Cov.: 32 AF XY: 0.0897 AC XY: 6672 AN XY: 74386

African (AFR) AF: 0.0212 AC: 881 AN: 41518

American (AMR) AF: 0.0842 AC: 1287 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3468

East Asian (EAS) AF: 0.0405 AC: 210 AN: 5184

South Asian (SAS) AF: 0.123 AC: 592 AN: 4818

European-Finnish (FIN) AF: 0.157 AC: 1655 AN: 10566

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8574 AN: 67986

Other (OTH) AF: 0.0631 AC: 133 AN: 2108

Alfa AF: 0.105 Hom.: 722

Bravo AF: 0.0805

TwinsUK AF: 0.108 AC: 401

ALSPAC AF: 0.119 AC: 460

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.124 AC: 1063

ExAC AF: 0.110 AC: 13366

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.108

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	INSULIN RESISTANCE, DIGENIC (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
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.40
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.24
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.075
MPC		0.12
ClinPred		0.019	T
GERP RS		2.9
PromoterAI		0.087	Neutral
Varity_R		0.075
gMVP		0.24
Mutation Taster		=97/3	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: rs1801282; hg19: chr3-12393125; COSMIC: COSV55140710;