rs6448226

Variant names:

• chr4-23835030-G-A
• rs6448226
• NM_013261.5:c.235-3279C>T

Variant summary

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

The NM_013261.5(PPARGC1A):​c.235-3279C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 151,930 control chromosomes in the GnomAD database, including 29,375 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 0.62 (29375 hom., cov: 32)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 16 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).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.235-3279C>T		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.235-3279C>T		intron_variant	Intron 2 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94327 AN: 151812 Hom.: 29367 Cov.: 32

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.637

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

GnomAD4 genome AF: 0.621 AC: 94377 AN: 151930 Hom.: 29375 Cov.: 32 AF XY: 0.620 AC XY: 46035 AN XY: 74252

African (AFR) AF: 0.594 AC: 24580 AN: 41398

American (AMR) AF: 0.684 AC: 10450 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2220 AN: 3468

East Asian (EAS) AF: 0.512 AC: 2638 AN: 5152

South Asian (SAS) AF: 0.530 AC: 2545 AN: 4804

European-Finnish (FIN) AF: 0.644 AC: 6790 AN: 10550

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43150 AN: 67968

Other (OTH) AF: 0.635 AC: 1341 AN: 2112

Alfa AF: 0.635 Hom.: 52194

Bravo AF: 0.625

Asia WGS AF: 0.553 AC: 1919 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.38
PhyloP100		-0.37
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: rs6448226; hg19: chr4-23836653;