rs12374310

Variant names:

• chr4-23852526-G-C
• rs12374310
• NM_013261.5:c.235-20775C>G

Variant summary

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

The NM_013261.5(PPARGC1A):​c.235-20775C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 151,868 control chromosomes in the GnomAD database, including 33,538 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 0.66 (33538 hom., cov: 30)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• Publications: 12 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.235-20775C>G		intron_variant	Intron 2 of 12	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.235-20775C>G		intron_variant	Intron 2 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99426 AN: 151750 Hom.: 33474 Cov.: 30

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.624

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

GnomAD4 genome AF: 0.655 AC: 99547 AN: 151868 Hom.: 33538 Cov.: 30 AF XY: 0.655 AC XY: 48632 AN XY: 74210

African (AFR) AF: 0.817 AC: 33857 AN: 41430

American (AMR) AF: 0.547 AC: 8339 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2123 AN: 3466

East Asian (EAS) AF: 0.453 AC: 2322 AN: 5122

South Asian (SAS) AF: 0.596 AC: 2864 AN: 4806

European-Finnish (FIN) AF: 0.662 AC: 6991 AN: 10556

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41054 AN: 67926

Other (OTH) AF: 0.629 AC: 1326 AN: 2108

Alfa AF: 0.644 Hom.: 3983

Bravo AF: 0.648

Asia WGS AF: 0.572 AC: 1991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.13
DANN	Benign	0.69
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12374310; hg19: chr4-23854149;