chr3-12433975-A-C

Variant names:

• chr3-12433975-A-C
• rs587780424
• NM_138711.6:c.1258A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_138711.6(PPARG):​c.1258A>C​(p.Lys420Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPARG NM_138711.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.97
• Publications: 16 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPARG gene, where missense mutations are typically associated with disease (based on misZ statistic). 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: 3.0978 (above the threshold of 3.09). GenCC associations: The gene is linked to PPARG-related familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy, lipodystrophy.

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.1258A>C	p.Lys420Gln	missense	Exon 8 of 8	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.1348A>C	p.Lys450Gln	missense	Exon 7 of 7	NP_056953.2
	PPARG	NM_001354666.3		c.1258A>C	p.Lys420Gln	missense	Exon 8 of 8	NP_001341595.2	E9PFV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.1258A>C	p.Lys420Gln	missense	Exon 8 of 8	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000287820.10	TSL:1	c.1348A>C	p.Lys450Gln	missense	Exon 7 of 7	ENSP00000287820.6	P37231-1
	PPARG	ENST00000397010.7	TSL:1	c.1258A>C	p.Lys420Gln	missense	Exon 8 of 8	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.035
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.50
Sift	Benign	0.78	T
Sift4G	Benign	0.61	T
Polyphen		0.31	B
Vest4		0.17
MutPred		0.44		Loss of ubiquitination at K450 (P = 0.0148)
MVP		0.87
MPC		1.2
ClinPred		0.78	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.50
Mutation Taster		=38/62	disease causing

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: rs587780424; hg19: chr3-12475474; COSMIC: COSV55144149;