rs2932976

Positions:

• chr4-23820705-G-A
• chr4-23820705-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

The ENST00000264867.7(PPARGC1A):​c.877+3575C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 347,638 control chromosomes in the GnomAD database, including 11,521 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4457 hom., cov: 32)
  • Exomes 𝑓: 0.25 (7064 hom.)
• Consequence: PPARGC1A ENST00000264867.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

Genes affected

PPARGC1A (HGNC:9237): (PPARG coactivator 1 alpha) The protein encoded by this gene is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with PPARgamma, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.877+3575C>T		intron_variant		ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.877+3575C>T		intron_variant		1	NM_013261.5	ENSP00000264867	P1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33536 AN: 151892 Hom.: 4457 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0834

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.254 AC: 49605 AN: 195626 Hom.: 7064 AF XY: 0.247 AC XY: 28281 AN XY: 114416

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.0785

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.221 AC: 33557 AN: 152012 Hom.: 4457 Cov.: 32 AF XY: 0.225 AC XY: 16721 AN XY: 74284

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.0828

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.212

Alfa AF: 0.244 Hom.: 6329

Bravo AF: 0.212

Asia WGS AF: 0.174 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs2932976; hg19: chr4-23822328; COSMIC: COSV53527873; COSMIC: COSV53527873;