rs8192678

chr4-23814039-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013261.5(PPARGC1A):c.1444G>A(p.Gly482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,613,718 control chromosomes in the GnomAD database, including 88,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.26 (6219 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82752 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.21

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026910305).
• BP6: Variant 4-23814039-C-T is Benign according to our data. Variant chr4-23814039-C-T is described in ClinVar as [Benign]. Clinvar id is 3060597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.1444G>A	p.Gly482Ser	missense_variant	8/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1444G>A	p.Gly482Ser	missense_variant	8/13	1	NM_013261.5	P1
PPARGC1A	ENST00000613098.4	c.1063G>A	p.Gly355Ser	missense_variant	7/12	1
PPARGC1A	ENST00000506055.5	c.*659G>A		3_prime_UTR_variant, NMD_transcript_variant	8/13	1
PPARGC1A	ENST00000509702.5	n.1484G>A		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39997 AN: 151906 Hom.: 6228 Cov.: 32

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.309 AC: 77425 AN: 250648 Hom.: 12728 AF XY: 0.314 AC XY: 42497 AN XY: 135426

Gnomad AFR exome AF: 0.0864

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.426

Gnomad SAS exome AF: 0.268

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.331 AC: 484463 AN: 1461694 Hom.: 82752 Cov.: 55 AF XY: 0.330 AC XY: 240299 AN XY: 727168

Gnomad4 AFR exome AF: 0.0832

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.325

GnomAD4 genome AF: 0.263 AC: 39981 AN: 152024 Hom.: 6219 Cov.: 32 AF XY: 0.262 AC XY: 19498 AN XY: 74282

Gnomad4 AFR AF: 0.0945

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.303

Alfa AF: 0.323 Hom.: 15477

Bravo AF: 0.260

TwinsUK AF: 0.353 AC: 1310

ALSPAC AF: 0.351 AC: 1352

ESP6500AA AF: 0.103 AC: 455

ESP6500EA AF: 0.347 AC: 2988

ExAC AF: 0.308 AC: 37387

Asia WGS AF: 0.329 AC: 1145 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPARGC1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	16
Dann	Benign	0.38
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.0	N;.
REVEL	Benign	0.10
Sift	Benign	1.0	T;.
Sift4G	Benign	0.85	T;T
Polyphen		0.053	B;.
Vest4		0.041
MPC		0.22
ClinPred		0.0068	T
GERP RS		6.0
Varity_R		0.030
gMVP		0.096

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

Publications

LitVar

Other links and lift over

dbSNP: rs8192678; hg19: chr4-23815662; COSMIC: COSV53527108; COSMIC: COSV53527108;