rs3774909

Positions:

• chr4-23827085-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_013261.5(PPARGC1A):​c.757+1315G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 152,246 control chromosomes in the GnomAD database, including 113 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 0.038 (113 hom., cov: 32)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0375 (5712/152246) while in subpopulation NFE AF= 0.0492 (3344/68004). AF 95% confidence interval is 0.0478. There are 113 homozygotes in gnomad4. There are 2738 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5712 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.757+1315G>A		intron_variant		ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.757+1315G>A		intron_variant		1	NM_013261.5	P1

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5706 AN: 152128 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.00889

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0406

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

GnomAD4 genome AF: 0.0375 AC: 5712 AN: 152246 Hom.: 113 Cov.: 32 AF XY: 0.0368 AC XY: 2738 AN XY: 74440

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0356

Gnomad4 ASJ AF: 0.0596

Gnomad4 EAS AF: 0.00891

Gnomad4 SAS AF: 0.0386

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0492

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0467 Hom.: 226

Bravo AF: 0.0370

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.66

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: rs3774909; hg19: chr4-23828708;