4-23884700-G-T

Variant names:

• chr4-23884700-G-T
• rs2946385
• NM_013261.5:c.234+52C>A

Variant summary

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

The NM_013261.5(PPARGC1A):​c.234+52C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,522,370 control chromosomes in the GnomAD database, including 126,848 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 0.41 (12875 hom., cov: 33)
  • Exomes 𝑓: 0.40 (113973 hom.)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 23 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.234+52C>A		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.234+52C>A		intron_variant	Intron 2 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61551 AN: 151914 Hom.: 12850 Cov.: 33

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.447

GnomAD2 exomes AF: 0.367 AC: 80491 AN: 219080 AF XY: 0.373

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.373

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.405 AC: 554640 AN: 1370338 Hom.: 113973 Cov.: 24 AF XY: 0.405 AC XY: 274534 AN XY: 678634

African (AFR) AF: 0.470 AC: 14726 AN: 31328

American (AMR) AF: 0.225 AC: 8986 AN: 39872

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 10549 AN: 23196

East Asian (EAS) AF: 0.364 AC: 13890 AN: 38142

South Asian (SAS) AF: 0.358 AC: 26755 AN: 74702

European-Finnish (FIN) AF: 0.268 AC: 13330 AN: 49750

Middle Eastern (MID) AF: 0.514 AC: 2798 AN: 5448

European-Non Finnish (NFE) AF: 0.419 AC: 440190 AN: 1051590

Other (OTH) AF: 0.416 AC: 23416 AN: 56310

GnomAD4 genome AF: 0.405 AC: 61612 AN: 152032 Hom.: 12875 Cov.: 33 AF XY: 0.397 AC XY: 29489 AN XY: 74302

African (AFR) AF: 0.463 AC: 19221 AN: 41478

American (AMR) AF: 0.323 AC: 4928 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3470

East Asian (EAS) AF: 0.354 AC: 1826 AN: 5158

South Asian (SAS) AF: 0.342 AC: 1649 AN: 4824

European-Finnish (FIN) AF: 0.268 AC: 2826 AN: 10564

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 28076 AN: 67958

Other (OTH) AF: 0.450 AC: 950 AN: 2112

Alfa AF: 0.411 Hom.: 37743

Bravo AF: 0.413

Asia WGS AF: 0.353 AC: 1233 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	0.14
DANN	Benign	0.41
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs2946385; hg19: chr4-23886323; COSMIC: COSV53527875; COSMIC: COSV53527875;