rs756523051
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_138711.6(PPARG):āc.1295A>Gā(p.Lys432Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.0000048 ( 0 hom. )
Consequence
PPARG
NM_138711.6 missense
NM_138711.6 missense
Scores
9
3
7
Clinical Significance
Conservation
PhyloP100: 7.42
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPARG. . Gene score misZ 2.1192 (greater than the threshold 3.09). Trascript score misZ 3.0978 (greater than threshold 3.09). GenCC has associacion of gene with PPARG-related familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887
BS2
High AC in GnomAdExome4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPARG | NM_138711.6 | c.1295A>G | p.Lys432Arg | missense_variant | 8/8 | ENST00000651735.1 | NP_619725.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PPARG | ENST00000651735.1 | c.1295A>G | p.Lys432Arg | missense_variant | 8/8 | NM_138711.6 | ENSP00000498313 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251440Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135880
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727246
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Feb 17, 2017 | ACMG Criteria:PP3 (8 predictors), PS3 (functional study with machine learning, PMID:27749844) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;.;.;.;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;.;.;.;.;.;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;.;.;.;.;.;L
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.;.;.;N;N;N
REVEL
Pathogenic
Sift
Benign
T;T;T;.;.;.;T;T;T
Sift4G
Benign
T;T;T;.;.;.;T;T;T
Polyphen
1.0
.;.;.;.;.;.;.;.;D
Vest4
MutPred
0.70
.;.;.;.;.;.;.;.;Loss of ubiquitination at K462 (P = 0.0381);
MVP
MPC
1.9
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at