rs3774908

Variant names:

• chr4-23827311-A-G
• rs3774908
• NM_013261.5:c.757+1089T>C

Variant summary

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

The NM_001330751.2(PPARGC1A):​c.772+1089T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 152,158 control chromosomes in the GnomAD database, including 635 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 0.088 (635 hom., cov: 32)
• Consequence: PPARGC1A NM_001330751.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.638
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330751.2. 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.757+1089T>C		intron	N/A	NP_037393.1
	PPARGC1A	NM_001330751.2		c.772+1089T>C		intron	N/A	NP_001317680.1
	PPARGC1A	NM_001354825.2		c.772+1089T>C		intron	N/A	NP_001341754.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.757+1089T>C		intron	N/A	ENSP00000264867.2
	PPARGC1A	ENST00000613098.4	TSL:1	c.376+1089T>C		intron	N/A	ENSP00000481498.1
	PPARGC1A	ENST00000506055.5	TSL:1	n.757+1089T>C		intron	N/A	ENSP00000423075.1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13364 AN: 152040 Hom.: 636 Cov.: 32

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0998

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.0939

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

GnomAD4 genome AF: 0.0879 AC: 13369 AN: 152158 Hom.: 635 Cov.: 32 AF XY: 0.0935 AC XY: 6954 AN XY: 74394

African (AFR) AF: 0.0735 AC: 3052 AN: 41520

American (AMR) AF: 0.101 AC: 1545 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0998 AC: 346 AN: 3468

East Asian (EAS) AF: 0.191 AC: 983 AN: 5150

South Asian (SAS) AF: 0.150 AC: 722 AN: 4822

European-Finnish (FIN) AF: 0.129 AC: 1367 AN: 10600

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0738 AC: 5018 AN: 68004

Other (OTH) AF: 0.0924 AC: 195 AN: 2110

Alfa AF: 0.0778 Hom.: 1686

Bravo AF: 0.0833

Asia WGS AF: 0.146 AC: 507 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.96
DANN	Benign	0.42
PhyloP100		-0.64
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: rs3774908; hg19: chr4-23828934;