chr3-12402345-A-G

Variant names:

• chr3-12402345-A-G
• rs4135275
• NM_138711.6:c.530-3537A>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.530-3537A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,054 control chromosomes in the GnomAD database, including 3,206 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 0.18 (3206 hom., cov: 32)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.254
• Publications: 30 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.473 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.530-3537A>G		intron	N/A	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.620-3537A>G		intron	N/A	NP_056953.2
	PPARG	NM_001354666.3		c.530-3537A>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.530-3537A>G		intron	N/A	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000287820.10	TSL:1	c.620-3537A>G		intron	N/A	ENSP00000287820.6	P37231-1
	PPARG	ENST00000397010.7	TSL:1	c.530-3537A>G		intron	N/A	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26773 AN: 151936 Hom.: 3212 Cov.: 32

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.176 AC: 26762 AN: 152054 Hom.: 3206 Cov.: 32 AF XY: 0.180 AC XY: 13396 AN XY: 74328

African (AFR) AF: 0.0653 AC: 2711 AN: 41512

American (AMR) AF: 0.236 AC: 3612 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 442 AN: 3472

East Asian (EAS) AF: 0.489 AC: 2523 AN: 5156

South Asian (SAS) AF: 0.462 AC: 2220 AN: 4808

European-Finnish (FIN) AF: 0.135 AC: 1420 AN: 10552

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13265 AN: 67960

Other (OTH) AF: 0.172 AC: 364 AN: 2112

Alfa AF: 0.194 Hom.: 10295

Bravo AF: 0.174

Asia WGS AF: 0.432 AC: 1502 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.69
PhyloP100		-0.25
Mutation Taster		=100/0	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: rs4135275; hg19: chr3-12443844;