rs8192678

Positions:

chr4-23814039-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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 (no stars). 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

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.21

Variant links:

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]

PPARGC1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
PPARGC1A	NM_013261.5 linkuse as main transcript	c.1444G>A	p.Gly482Ser	missense_variant	8/13	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7 linkuse as main transcript	c.1444G>A	p.Gly482Ser	missense_variant	8/13	1	NM_013261.5	ENSP00000264867	P1	Q9UBK2-1
PPARGC1A	ENST00000613098.4 linkuse as main transcript	c.1063G>A	p.Gly355Ser	missense_variant	7/12	1		ENSP00000481498		Q9UBK2-9
PPARGC1A	ENST00000506055.5 linkuse as main transcript	c.*659G>A		3_prime_UTR_variant, NMD_transcript_variant	8/13	1		ENSP00000423075		Q9UBK2-2
PPARGC1A	ENST00000509702.5 linkuse as main transcript	n.1484G>A		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39997

AN:

151906

Hom.:

6228

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.330

AC XY:

240299

AN XY:

727168

show subpopulations

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.:

AF XY:

0.262

AC XY:

19498

AN XY:

74282

show subpopulations

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: no assertion criteria provided

LINK: link

Submissions by phenotype

PPARGC1A-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.38

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over