NM_013261.5:c.757+1315G>A

Variant names:

• chr4-23827085-C-T
• rs3774909
• NM_013261.5:c.757+1315G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_013261.5(PPARGC1A):​c.757+1315G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 152,246 control chromosomes in the GnomAD database, including 113 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 0.038 (113 hom., cov: 32)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• Publications: 9 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=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0375 (5712/152246) while in subpopulation NFE AF = 0.0492 (3344/68004). AF 95% confidence interval is 0.0478. There are 113 homozygotes in GnomAd4. There are 2738 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5712 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.757+1315G>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.757+1315G>A		intron_variant	Intron 5 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5706 AN: 152128 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.00889

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0406

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

GnomAD4 genome AF: 0.0375 AC: 5712 AN: 152246 Hom.: 113 Cov.: 32 AF XY: 0.0368 AC XY: 2738 AN XY: 74440

African (AFR) AF: 0.0203 AC: 844 AN: 41558

American (AMR) AF: 0.0356 AC: 544 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 207 AN: 3472

East Asian (EAS) AF: 0.00891 AC: 46 AN: 5160

South Asian (SAS) AF: 0.0386 AC: 186 AN: 4822

European-Finnish (FIN) AF: 0.0386 AC: 410 AN: 10618

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3344 AN: 68004

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0463 Hom.: 293

Bravo AF: 0.0370

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.66
PhyloP100		0.050
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: rs3774909; hg19: chr4-23828708;