4-23825622-A-T

Variant names:

• chr4-23825622-A-T
• rs2970855
• NM_013261.5:c.758-1114T>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.758-1114T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 151,880 control chromosomes in the GnomAD database, including 30,421 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 0.63 (30421 hom., cov: 32)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 6 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=-0.55).
• BA1: GnomAd4 highest subpopulation (AMR) 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.758-1114T>A		intron_variant	Intron 5 of 12	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.758-1114T>A		intron_variant	Intron 5 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95836 AN: 151762 Hom.: 30407 Cov.: 32

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.645

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

GnomAD4 genome AF: 0.631 AC: 95900 AN: 151880 Hom.: 30421 Cov.: 32 AF XY: 0.630 AC XY: 46769 AN XY: 74236

African (AFR) AF: 0.594 AC: 24626 AN: 41446

American (AMR) AF: 0.691 AC: 10536 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2284 AN: 3470

East Asian (EAS) AF: 0.508 AC: 2614 AN: 5144

South Asian (SAS) AF: 0.539 AC: 2591 AN: 4810

European-Finnish (FIN) AF: 0.653 AC: 6886 AN: 10540

Middle Eastern (MID) AF: 0.652 AC: 189 AN: 290

European-Non Finnish (NFE) AF: 0.652 AC: 44244 AN: 67906

Other (OTH) AF: 0.642 AC: 1351 AN: 2104

Alfa AF: 0.653 Hom.: 4014

Bravo AF: 0.635

Asia WGS AF: 0.567 AC: 1963 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		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: rs2970855; hg19: chr4-23827245;