chr3-12381767-T-C

Variant names:

• chr3-12381767-T-C
• rs4135263
• NM_138711.6:c.390+276T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138711.6(PPARG):​c.390+276T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,064 control chromosomes in the GnomAD database, including 1,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1657 hom., cov: 32)
• Consequence: PPARG NM_138711.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.125
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-12381767-T-C is Benign according to our data. Variant chr3-12381767-T-C is described in ClinVar as Benign. ClinVar VariationId is 1261529.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	NM_138711.6	MANE Select	c.390+276T>C		intron	N/A	NP_619725.3
	PPARG	NM_015869.5		c.480+276T>C		intron	N/A	NP_056953.2
	PPARG	NM_001354666.3		c.390+276T>C		intron	N/A	NP_001341595.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.390+276T>C		intron	N/A	ENSP00000498313.1
	PPARG	ENST00000287820.10	TSL:1	c.480+276T>C		intron	N/A	ENSP00000287820.6
	PPARG	ENST00000397010.7	TSL:1	c.390+276T>C		intron	N/A	ENSP00000380205.3

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21234 AN: 151948 Hom.: 1652 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.146

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.140 AC: 21261 AN: 152064 Hom.: 1657 Cov.: 32 AF XY: 0.140 AC XY: 10392 AN XY: 74322

African (AFR) AF: 0.114 AC: 4720 AN: 41490

American (AMR) AF: 0.215 AC: 3287 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5170

South Asian (SAS) AF: 0.114 AC: 549 AN: 4820

European-Finnish (FIN) AF: 0.148 AC: 1565 AN: 10554

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9938 AN: 67988

Other (OTH) AF: 0.145 AC: 306 AN: 2114

Alfa AF: 0.153 Hom.: 2081

Bravo AF: 0.147

Asia WGS AF: 0.0620 AC: 215 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.50
PhyloP100		0.13
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: rs4135263; hg19: chr3-12423266;