4-23795377-C-T

Variant names:

• chr4-23795377-C-T
• rs6821591
• NM_013261.5:c.*445G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_013261.5(PPARGC1A):​c.*445G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 147,626 control chromosomes in the GnomAD database, including 21,378 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 0.53 (21329 hom., cov: 24)
  • Exomes 𝑓: 0.45 (49 hom.)
• Consequence: PPARGC1A NM_013261.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• Publications: 31 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.*445G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.*445G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_013261.5	ENSP00000264867.2
PPARGC1A	ENST00000613098.4	c.*445G>A		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000481498.1
PPARGC1A	ENST00000509702.5	n.2433+449G>A		intron_variant	Intron 13 of 14	5

Frequencies

GnomAD3 genomes AF: 0.533 AC: 78444 AN: 147122 Hom.: 21328 Cov.: 24

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.645

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.567

GnomAD4 exome AF: 0.452 AC: 196 AN: 434 Hom.: 49 Cov.: 0 AF XY: 0.461 AC XY: 119 AN XY: 258

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.833 AC: 5 AN: 6

European-Finnish (FIN) AF: 0.424 AC: 111 AN: 262

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.480 AC: 72 AN: 150

Other (OTH) AF: 0.417 AC: 5 AN: 12

GnomAD4 genome AF: 0.533 AC: 78468 AN: 147192 Hom.: 21329 Cov.: 24 AF XY: 0.534 AC XY: 38165 AN XY: 71480

African (AFR) AF: 0.595 AC: 23726 AN: 39890

American (AMR) AF: 0.497 AC: 7266 AN: 14624

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2166 AN: 3456

East Asian (EAS) AF: 0.699 AC: 3445 AN: 4930

South Asian (SAS) AF: 0.625 AC: 2877 AN: 4604

European-Finnish (FIN) AF: 0.461 AC: 4331 AN: 9400

Middle Eastern (MID) AF: 0.643 AC: 180 AN: 280

European-Non Finnish (NFE) AF: 0.491 AC: 32923 AN: 67084

Other (OTH) AF: 0.566 AC: 1148 AN: 2030

Alfa AF: 0.516 Hom.: 54935

Bravo AF: 0.537

Asia WGS AF: 0.651 AC: 2268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		2.4
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: rs6821591; hg19: chr4-23797000;