3-12351626-C-G

Variant names:

• chr3-12351626-C-G
• rs1801282
• ENST00000287820.10:c.34C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138711.6(PPARG):​c.-8-28078C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,609,512 control chromosomes in the GnomAD database, including 11,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (771 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10627 hom.)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.395
• Publications: 1987 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011972487).
• BP6: Variant 3-12351626-C-G is Benign according to our data. Variant chr3-12351626-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 130019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARG	NM_138711.6	c.-8-28078C>G		intron_variant	Intron 2 of 7	ENST00000651735.1	NP_619725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARG	ENST00000651735.1	c.-8-28078C>G		intron_variant	Intron 2 of 7		NM_138711.6	ENSP00000498313.1

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13577 AN: 152022 Hom.: 768 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.0638

GnomAD2 exomes AF: 0.110 AC: 27634 AN: 251078 AF XY: 0.111

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0565

Gnomad EAS exome AF: 0.0383

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.115 AC: 168301 AN: 1457372 Hom.: 10627 Cov.: 31 AF XY: 0.117 AC XY: 84648 AN XY: 725298

African (AFR) AF: 0.0154 AC: 514 AN: 33424

American (AMR) AF: 0.118 AC: 5268 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 1467 AN: 26122

East Asian (EAS) AF: 0.0360 AC: 1427 AN: 39672

South Asian (SAS) AF: 0.123 AC: 10585 AN: 86168

European-Finnish (FIN) AF: 0.170 AC: 9051 AN: 53378

Middle Eastern (MID) AF: 0.0626 AC: 361 AN: 5764

European-Non Finnish (NFE) AF: 0.121 AC: 133539 AN: 1107902

Other (OTH) AF: 0.101 AC: 6089 AN: 60226

GnomAD4 genome AF: 0.0892 AC: 13574 AN: 152140 Hom.: 771 Cov.: 32 AF XY: 0.0897 AC XY: 6672 AN XY: 74386

African (AFR) AF: 0.0212 AC: 881 AN: 41518

American (AMR) AF: 0.0842 AC: 1287 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3468

East Asian (EAS) AF: 0.0405 AC: 210 AN: 5184

South Asian (SAS) AF: 0.123 AC: 592 AN: 4818

European-Finnish (FIN) AF: 0.157 AC: 1655 AN: 10566

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8574 AN: 67986

Other (OTH) AF: 0.0631 AC: 133 AN: 2108

Alfa AF: 0.105 Hom.: 722

Bravo AF: 0.0805

TwinsUK AF: 0.108 AC: 401

ALSPAC AF: 0.119 AC: 460

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.124 AC: 1063

ExAC AF: 0.110 AC: 13366

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26049557, 26025336, 26273662, 25216344, 24319532, 23300871, 22800638, 24141935, 23633103, 28386678, 29632382, 28924543, 24447396, 11289055, 26551672, 23666678, 27398621, 11289057, 9792554, 21155004, 25157153, 22276212, 20591056, 17495181, 20930717, 9806549, 10973253, 10873398, 21833536, 20450366, 22378291, 10851250, 21795447, 20623456, 22575725, 19465486, 20368233, 21508507, 20424228, 12974743, 19178525, 22168210, 17187763, 22958899, 23161442) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

INSULIN RESISTANCE, DIGENIC Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Obesity Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

PPARG-related familial partial lipodystrophy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.40
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.24
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.075
MPC		0.12
ClinPred		0.019	T
GERP RS		2.9
PromoterAI		0.087	Neutral
Varity_R		0.075
gMVP		0.24
Mutation Taster		=97/3	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: rs1801282; hg19: chr3-12393125; COSMIC: COSV55140710;