chr3-12405769-G-A

Variant names:

• chr3-12405769-G-A
• rs73027210
• NM_138711.6:c.530-113G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_015869.5(PPARG):​c.620-113G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,037,274 control chromosomes in the GnomAD database, including 29 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 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (27 hom.)
• Consequence: PPARG NM_015869.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, Genomics England PanelApp
• 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=-0.83).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00413 (630/152368) while in subpopulation AMR AF = 0.0112 (172/15302). AF 95% confidence interval is 0.00987. There are 2 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	NM_138711.6	MANE Select	c.530-113G>A		intron	N/A	NP_619725.3
	PPARG	NM_015869.5		c.620-113G>A		intron	N/A	NP_056953.2
	PPARG	NM_001354666.3		c.530-113G>A		intron	N/A	NP_001341595.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.530-113G>A		intron	N/A	ENSP00000498313.1
	PPARG	ENST00000287820.10	TSL:1	c.620-113G>A		intron	N/A	ENSP00000287820.6
	PPARG	ENST00000397010.7	TSL:1	c.530-113G>A		intron	N/A	ENSP00000380205.3

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 628 AN: 152250 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00433 AC: 3829 AN: 884906 Hom.: 27 AF XY: 0.00415 AC XY: 1908 AN XY: 459424

African (AFR) AF: 0.00117 AC: 26 AN: 22228

American (AMR) AF: 0.00531 AC: 207 AN: 38960

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 432 AN: 22210

East Asian (EAS) AF: 0.00 AC: 0 AN: 35396

South Asian (SAS) AF: 0.000225 AC: 16 AN: 71234

European-Finnish (FIN) AF: 0.00185 AC: 75 AN: 40536

Middle Eastern (MID) AF: 0.00261 AC: 8 AN: 3070

European-Non Finnish (NFE) AF: 0.00472 AC: 2876 AN: 609792

Other (OTH) AF: 0.00456 AC: 189 AN: 41480

GnomAD4 genome AF: 0.00413 AC: 630 AN: 152368 Hom.: 2 Cov.: 32 AF XY: 0.00432 AC XY: 322 AN XY: 74496

African (AFR) AF: 0.000914 AC: 38 AN: 41590

American (AMR) AF: 0.0112 AC: 172 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00466 AC: 317 AN: 68042

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00436

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.52
PhyloP100		-0.040
Mutation Taster		=100/0	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: rs73027210; hg19: chr3-12447268;