3-12379590-C-T

Variant names:

• chr3-12379590-C-T
• rs28763893
• NM_138711.6:c.-8-114C>T

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.-8-114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 909,472 control chromosomes in the GnomAD database, including 10,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1607 hom., cov: 32)
  • Exomes 𝑓: 0.14 (8755 hom.)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.580
• Publications: 4 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 (BayesDel_noAF=-0.97).
• BP6: Variant 3-12379590-C-T is Benign according to our data. Variant chr3-12379590-C-T is described in ClinVar as [Benign]. Clinvar id is 1227468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARG	NM_138711.6	c.-8-114C>T		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.-8-114C>T		intron_variant	Intron 2 of 7		NM_138711.6	ENSP00000498313.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20982 AN: 152046 Hom.: 1602 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.142 AC: 107649 AN: 757306 Hom.: 8755 AF XY: 0.141 AC XY: 55987 AN XY: 397548

African (AFR) AF: 0.115 AC: 2220 AN: 19272

American (AMR) AF: 0.296 AC: 10253 AN: 34634

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 3436 AN: 20646

East Asian (EAS) AF: 0.000208 AC: 7 AN: 33670

South Asian (SAS) AF: 0.120 AC: 7883 AN: 65638

European-Finnish (FIN) AF: 0.141 AC: 5464 AN: 38742

Middle Eastern (MID) AF: 0.176 AC: 693 AN: 3942

European-Non Finnish (NFE) AF: 0.144 AC: 72520 AN: 503566

Other (OTH) AF: 0.139 AC: 5173 AN: 37196

GnomAD4 genome AF: 0.138 AC: 21011 AN: 152166 Hom.: 1607 Cov.: 32 AF XY: 0.138 AC XY: 10260 AN XY: 74388

African (AFR) AF: 0.114 AC: 4719 AN: 41530

American (AMR) AF: 0.211 AC: 3228 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 618 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5178

South Asian (SAS) AF: 0.106 AC: 510 AN: 4818

European-Finnish (FIN) AF: 0.149 AC: 1580 AN: 10586

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9817 AN: 67978

Other (OTH) AF: 0.143 AC: 302 AN: 2114

Alfa AF: 0.140 Hom.: 213

Bravo AF: 0.145

Asia WGS AF: 0.0570 AC: 198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.85
DANN	Benign	0.37
PhyloP100		-0.58
PromoterAI		0.038	Neutral
Mutation Taster		=100/0	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: rs28763893; hg19: chr3-12421089;