rs2305681

Variant names:

• chr4-23829299-T-C
• rs2305681
• NM_013261.5:c.552+164A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_013261.5(PPARGC1A):​c.552+164A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 152,308 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: 33)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09
• Publications: 5 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=-0.95).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0377 (5736/152308) while in subpopulation NFE AF = 0.0491 (3341/68024). AF 95% confidence interval is 0.0477. There are 113 homozygotes in GnomAd4. There are 2746 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5736 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.552+164A>G		intron_variant	Intron 4 of 12	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.552+164A>G		intron_variant	Intron 4 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5729 AN: 152190 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0411

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

GnomAD4 genome AF: 0.0377 AC: 5736 AN: 152308 Hom.: 113 Cov.: 33 AF XY: 0.0369 AC XY: 2746 AN XY: 74474

African (AFR) AF: 0.0208 AC: 865 AN: 41580

American (AMR) AF: 0.0357 AC: 546 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3470

East Asian (EAS) AF: 0.00909 AC: 47 AN: 5170

South Asian (SAS) AF: 0.0386 AC: 186 AN: 4822

European-Finnish (FIN) AF: 0.0388 AC: 412 AN: 10622

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0491 AC: 3341 AN: 68024

Other (OTH) AF: 0.0431 AC: 91 AN: 2112

Alfa AF: 0.0422 Hom.: 13

Bravo AF: 0.0372

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.029
DANN	Benign	0.36
PhyloP100		-2.1
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: rs2305681; hg19: chr4-23830922;