rs3856806

Variant names:

• chr3-12434058-C-T
• rs3856806
• NM_138711.6:c.1341C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015869.5(PPARG):​c.1431C>T​(p.His477His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,614,040 control chromosomes in the GnomAD database, including 13,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1153 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12668 hom.)
• Consequence: PPARG NM_015869.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.333
• Publications: 438 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-12434058-C-T is Benign according to our data. Variant chr3-12434058-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.333 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	NM_138711.6	MANE Select	c.1341C>T	p.His447His	synonymous	Exon 8 of 8	NP_619725.3
	PPARG	NM_015869.5		c.1431C>T	p.His477His	synonymous	Exon 7 of 7	NP_056953.2
	PPARG	NM_001354666.3		c.1341C>T	p.His447His	synonymous	Exon 8 of 8	NP_001341595.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.1341C>T	p.His447His	synonymous	Exon 8 of 8	ENSP00000498313.1
	PPARG	ENST00000287820.10	TSL:1	c.1431C>T	p.His477His	synonymous	Exon 7 of 7	ENSP00000287820.6
	PPARG	ENST00000397010.7	TSL:1	c.1341C>T	p.His447His	synonymous	Exon 8 of 8	ENSP00000380205.3

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17378 AN: 152060 Hom.: 1149 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0869

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.0895

GnomAD2 exomes AF: 0.134 AC: 33702 AN: 251322 AF XY: 0.136

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.128 AC: 187677 AN: 1461862 Hom.: 12668 Cov.: 32 AF XY: 0.129 AC XY: 93871 AN XY: 727234

African (AFR) AF: 0.0572 AC: 1914 AN: 33480

American (AMR) AF: 0.107 AC: 4765 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 1935 AN: 26134

East Asian (EAS) AF: 0.197 AC: 7821 AN: 39700

South Asian (SAS) AF: 0.144 AC: 12408 AN: 86256

European-Finnish (FIN) AF: 0.197 AC: 10507 AN: 53420

Middle Eastern (MID) AF: 0.0820 AC: 473 AN: 5768

European-Non Finnish (NFE) AF: 0.126 AC: 140514 AN: 1111988

Other (OTH) AF: 0.122 AC: 7340 AN: 60396

GnomAD4 genome AF: 0.114 AC: 17390 AN: 152178 Hom.: 1153 Cov.: 32 AF XY: 0.116 AC XY: 8636 AN XY: 74384

African (AFR) AF: 0.0638 AC: 2650 AN: 41532

American (AMR) AF: 0.0869 AC: 1328 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3468

East Asian (EAS) AF: 0.229 AC: 1186 AN: 5170

South Asian (SAS) AF: 0.151 AC: 729 AN: 4824

European-Finnish (FIN) AF: 0.200 AC: 2122 AN: 10584

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.131 AC: 8887 AN: 68000

Other (OTH) AF: 0.0895 AC: 189 AN: 2112

Alfa AF: 0.121 Hom.: 5727

Bravo AF: 0.102

Asia WGS AF: 0.133 AC: 463 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.114

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	Glioma susceptibility 1 (1)
-	-	1	INSULIN RESISTANCE, DIGENIC (1)
-	-	1	not specified (1)
-	-	1	Obesity (1)
-	-	1	PPARG POLYMORPHISM (1)
-	-	1	PPARG-related familial partial lipodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.1
DANN	Benign	0.53
PhyloP100		-0.33
Mutation Taster		=88/12	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: rs3856806; hg19: chr3-12475557; COSMIC: COSV55140736;