chr3-12371840-T-G

Variant names:

• chr3-12371840-T-G
• rs2120825
• NM_138711.6:c.-8-7864T>G

Variant summary

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

The NM_138711.6(PPARG):​c.-8-7864T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 678,070 control chromosomes in the GnomAD database, including 4,386 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 0.085 (764 hom., cov: 32)
  • Exomes 𝑓: 0.11 (3622 hom.)
• Consequence: PPARG NM_138711.6 intron
• Scores: Splicing: ADA: 0.0001114
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530
• Publications: 27 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.125 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.-8-7864T>G		intron	N/A	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.83-7864T>G		intron	N/A	NP_056953.2
	PPARG	NM_001354666.3		c.-8-7864T>G		intron	N/A	NP_001341595.2	E9PFV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.-8-7864T>G		intron	N/A	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000287820.10	TSL:1	c.83-7864T>G		intron	N/A	ENSP00000287820.6	P37231-1
	PPARG	ENST00000397010.7	TSL:1	c.-8-7864T>G		intron	N/A	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 12959 AN: 152150 Hom.: 761 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0776

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.101 AC: 13602 AN: 135256 AF XY: 0.103

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0532

Gnomad EAS exome AF: 0.0279

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0909

GnomAD4 exome AF: 0.107 AC: 56219 AN: 525802 Hom.: 3622 Cov.: 0 AF XY: 0.109 AC XY: 31241 AN XY: 285562

African (AFR) AF: 0.0177 AC: 270 AN: 15216

American (AMR) AF: 0.101 AC: 3410 AN: 33930

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 996 AN: 19306

East Asian (EAS) AF: 0.0265 AC: 800 AN: 30172

South Asian (SAS) AF: 0.133 AC: 8223 AN: 61722

European-Finnish (FIN) AF: 0.194 AC: 6191 AN: 31850

Middle Eastern (MID) AF: 0.0607 AC: 240 AN: 3954

European-Non Finnish (NFE) AF: 0.111 AC: 33503 AN: 300590

Other (OTH) AF: 0.0890 AC: 2586 AN: 29062

GnomAD4 genome AF: 0.0851 AC: 12958 AN: 152268 Hom.: 764 Cov.: 32 AF XY: 0.0882 AC XY: 6568 AN XY: 74428

African (AFR) AF: 0.0191 AC: 793 AN: 41592

American (AMR) AF: 0.0775 AC: 1186 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3466

East Asian (EAS) AF: 0.0327 AC: 169 AN: 5174

South Asian (SAS) AF: 0.134 AC: 645 AN: 4828

European-Finnish (FIN) AF: 0.199 AC: 2103 AN: 10584

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

European-Non Finnish (NFE) AF: 0.113 AC: 7714 AN: 68008

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.101 Hom.: 2569

Bravo AF: 0.0712

Asia WGS AF: 0.0570 AC: 198 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.70
PhyloP100		-0.053
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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: rs2120825; hg19: chr3-12413339; COSMIC: COSV55140725;