rs2290604

chr4-23828615-A-Gchr4-23828615-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_013261.5(PPARGC1A):c.553-11T>C variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0818 in 1,612,744 control chromosomes in the GnomAD database, including 6,241 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 0.084 (603 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5638 hom.)
• Consequence: PPARGC1A NM_013261.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.1777
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.553-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.553-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_013261.5	P1

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12798 AN: 152058 Hom.: 604 Cov.: 32

Gnomad AFR AF: 0.0597

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.0997

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0742

Gnomad OTH AF: 0.0923

GnomAD3 exomes AF: 0.100 AC: 25218 AN: 251006 Hom.: 1458 AF XY: 0.101 AC XY: 13759 AN XY: 135672

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.130

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0815 AC: 119102 AN: 1460568 Hom.: 5638 Cov.: 32 AF XY: 0.0833 AC XY: 60555 AN XY: 726722

Gnomad4 AFR exome AF: 0.0561

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0991

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.0700

Gnomad4 OTH exome AF: 0.0892

GnomAD4 genome AF: 0.0841 AC: 12794 AN: 152176 Hom.: 603 Cov.: 32 AF XY: 0.0895 AC XY: 6655 AN XY: 74386

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.0998

Gnomad4 ASJ AF: 0.0997

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0742

Gnomad4 OTH AF: 0.0908

Alfa AF: 0.0733 Hom.: 164

Bravo AF: 0.0792

Asia WGS AF: 0.145 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.050		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: rs2290604; hg19: chr4-23830238; COSMIC: COSV53524555; COSMIC: COSV53524555;