4-23960408-A-G

Variant names:

• chr4-23960408-A-G
• rs9291455
• NM_001330751.2:c.70-75477T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330751.2(PPARGC1A):​c.70-75477T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 151,900 control chromosomes in the GnomAD database, including 42,714 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 0.74 (42714 hom., cov: 31)
• Consequence: PPARGC1A NM_001330751.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_001330751.2	c.70-75477T>C		intron_variant	Intron 3 of 14		NP_001317680.1
PPARGC1A	NM_001354825.2	c.70-75477T>C		intron_variant	Intron 2 of 13		NP_001341754.1
PPARGC1A	NM_001354827.2	c.70-75477T>C		intron_variant	Intron 2 of 13		NP_001341756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112629 AN: 151782 Hom.: 42710 Cov.: 31

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.780

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

GnomAD4 genome AF: 0.742 AC: 112670 AN: 151900 Hom.: 42714 Cov.: 31 AF XY: 0.739 AC XY: 54858 AN XY: 74234

African (AFR) AF: 0.596 AC: 24666 AN: 41390

American (AMR) AF: 0.665 AC: 10148 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2857 AN: 3470

East Asian (EAS) AF: 0.695 AC: 3557 AN: 5118

South Asian (SAS) AF: 0.776 AC: 3736 AN: 4816

European-Finnish (FIN) AF: 0.779 AC: 8226 AN: 10566

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56904 AN: 67978

Other (OTH) AF: 0.783 AC: 1650 AN: 2108

Alfa AF: 0.795 Hom.: 102056

Bravo AF: 0.726

Asia WGS AF: 0.736 AC: 2560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.3
DANN	Benign	0.53
PhyloP100		0.070

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9291455; hg19: chr4-23962031;