4-23886996-A-G

Variant names:

• chr4-23886996-A-G
• rs2970876
• NM_013261.5:c.55-2065T>C

Variant summary

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

The NM_013261.5(PPARGC1A):​c.55-2065T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 152,034 control chromosomes in the GnomAD database, including 24,820 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 0.56 (24820 hom., cov: 32)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 4 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013261.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	NM_013261.5	MANE Select	c.55-2065T>C		intron	N/A	NP_037393.1	Q9UBK2-1
	PPARGC1A	NM_001330751.2		c.70-2065T>C		intron	N/A	NP_001317680.1	Q9UBK2-3
	PPARGC1A	NM_001354825.2		c.70-2065T>C		intron	N/A	NP_001341754.1	Q9UBK2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.55-2065T>C		intron	N/A	ENSP00000264867.2	Q9UBK2-1
	PPARGC1A	ENST00000506055.5	TSL:1	n.55-2065T>C		intron	N/A	ENSP00000423075.1	Q9UBK2-2
	PPARGC1A	ENST00000513205.5	TSL:1	n.55-2065T>C		intron	N/A	ENSP00000421632.1	Q9UBK2-8

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84544 AN: 151916 Hom.: 24783 Cov.: 32

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.557 AC: 84626 AN: 152034 Hom.: 24820 Cov.: 32 AF XY: 0.549 AC XY: 40838 AN XY: 74324

African (AFR) AF: 0.743 AC: 30783 AN: 41456

American (AMR) AF: 0.528 AC: 8067 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1917 AN: 3470

East Asian (EAS) AF: 0.533 AC: 2757 AN: 5168

South Asian (SAS) AF: 0.482 AC: 2321 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3832 AN: 10554

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33124 AN: 67976

Other (OTH) AF: 0.550 AC: 1163 AN: 2114

Alfa AF: 0.519 Hom.: 32162

Bravo AF: 0.581

Asia WGS AF: 0.508 AC: 1767 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.7
DANN	Benign	0.58
PhyloP100		1.7
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: rs2970876; hg19: chr4-23888619;