chr4-23814301-T-C

Variant names:

• chr4-23814301-T-C
• rs2970847
• NM_013261.5:c.1182A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_013261.5(PPARGC1A):​c.1182A>G​(p.Thr394Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 1,613,878 control chromosomes in the GnomAD database, including 532,364 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 0.86 (56415 hom., cov: 31)
  • Exomes 𝑓: 0.81 (475949 hom.)
• Consequence: PPARGC1A NM_013261.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.86
• Publications: 88 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 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.1182A>G	p.Thr394Thr	synonymous	Exon 8 of 13	NP_037393.1	Q9UBK2-1
	PPARGC1A	NM_001330751.2		c.1197A>G	p.Thr399Thr	synonymous	Exon 10 of 15	NP_001317680.1	Q9UBK2-3
	PPARGC1A	NM_001354825.2		c.1197A>G	p.Thr399Thr	synonymous	Exon 9 of 14	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.1182A>G	p.Thr394Thr	synonymous	Exon 8 of 13	ENSP00000264867.2	Q9UBK2-1
	PPARGC1A	ENST00000613098.4	TSL:1	c.801A>G	p.Thr267Thr	synonymous	Exon 7 of 12	ENSP00000481498.1	Q9UBK2-9
	PPARGC1A	ENST00000506055.5	TSL:1	n.*397A>G		non_coding_transcript_exon	Exon 8 of 13	ENSP00000423075.1	Q9UBK2-2

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130366 AN: 151952 Hom.: 56355 Cov.: 31

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.870

GnomAD2 exomes AF: 0.837 AC: 209723 AN: 250528 AF XY: 0.833

Gnomad AFR exome AF: 0.966

Gnomad AMR exome AF: 0.912

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 0.771

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.839

GnomAD4 exome AF: 0.806 AC: 1177533 AN: 1461808 Hom.: 475949 Cov.: 74 AF XY: 0.807 AC XY: 587211 AN XY: 727214

African (AFR) AF: 0.970 AC: 32479 AN: 33474

American (AMR) AF: 0.909 AC: 40627 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 22936 AN: 26136

East Asian (EAS) AF: 0.779 AC: 30914 AN: 39694

South Asian (SAS) AF: 0.846 AC: 72932 AN: 86256

European-Finnish (FIN) AF: 0.841 AC: 44921 AN: 53406

Middle Eastern (MID) AF: 0.853 AC: 4917 AN: 5766

European-Non Finnish (NFE) AF: 0.790 AC: 878271 AN: 1111964

Other (OTH) AF: 0.820 AC: 49536 AN: 60394

GnomAD4 genome AF: 0.858 AC: 130486 AN: 152070 Hom.: 56415 Cov.: 31 AF XY: 0.860 AC XY: 63918 AN XY: 74298

African (AFR) AF: 0.964 AC: 40000 AN: 41514

American (AMR) AF: 0.885 AC: 13525 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.877 AC: 3043 AN: 3470

East Asian (EAS) AF: 0.770 AC: 3958 AN: 5138

South Asian (SAS) AF: 0.846 AC: 4064 AN: 4806

European-Finnish (FIN) AF: 0.841 AC: 8887 AN: 10566

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54227 AN: 67974

Other (OTH) AF: 0.871 AC: 1842 AN: 2114

Alfa AF: 0.821 Hom.: 155515

Bravo AF: 0.865

Asia WGS AF: 0.854 AC: 2971 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.51
PhyloP100		-1.9
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: rs2970847; hg19: chr4-23815924; COSMIC: COSV53534255; COSMIC: COSV53534255;