4-23814301-T-C

Variant names:

• chr4-23814301-T-C
• rs2970847
• NM_013261.5:c.1182A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_013261.5(PPARGC1A):​c.1182A>G​(p.Thr394Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 1,613,878 control chromosomes in the GnomAD database, including 532,364 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 0.86 (56415 hom., cov: 31)
  • Exomes 𝑓: 0.81 (475949 hom.)
• Consequence: PPARGC1A NM_013261.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.86

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.1182A>G	p.Thr394Thr	synonymous_variant	Exon 8 of 13	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1182A>G	p.Thr394Thr	synonymous_variant	Exon 8 of 13	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130366 AN: 151952 Hom.: 56355 Cov.: 31

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.870

GnomAD3 exomes AF: 0.837 AC: 209723 AN: 250528 Hom.: 88189 AF XY: 0.833 AC XY: 112752 AN XY: 135336

Gnomad AFR exome AF: 0.966

Gnomad AMR exome AF: 0.912

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 0.771

Gnomad SAS exome AF: 0.848

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.806 AC: 1177533 AN: 1461808 Hom.: 475949 Cov.: 74 AF XY: 0.807 AC XY: 587211 AN XY: 727214

Gnomad4 AFR exome AF: 0.970

Gnomad4 AMR exome AF: 0.909

Gnomad4 ASJ exome AF: 0.878

Gnomad4 EAS exome AF: 0.779

Gnomad4 SAS exome AF: 0.846

Gnomad4 FIN exome AF: 0.841

Gnomad4 NFE exome AF: 0.790

Gnomad4 OTH exome AF: 0.820

GnomAD4 genome AF: 0.858 AC: 130486 AN: 152070 Hom.: 56415 Cov.: 31 AF XY: 0.860 AC XY: 63918 AN XY: 74298

Gnomad4 AFR AF: 0.964

Gnomad4 AMR AF: 0.885

Gnomad4 ASJ AF: 0.877

Gnomad4 EAS AF: 0.770

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.841

Gnomad4 NFE AF: 0.798

Gnomad4 OTH AF: 0.871

Alfa AF: 0.820 Hom.: 63170

Bravo AF: 0.865

Asia WGS AF: 0.854 AC: 2971 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.51

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: rs2970847; hg19: chr4-23815924; COSMIC: COSV53534255; COSMIC: COSV53534255;