rs3736265

Positions:

Variant summary

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

The ENST00000264867.7(PPARGC1A):c.1835C>T(p.Thr612Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 1,613,862 control chromosomes in the GnomAD database, including 4,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.073 ( 458 hom., cov: 31)

Exomes 𝑓: 0.065 ( 4021 hom. )

Consequence

PPARGC1A
ENST00000264867.7 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.51

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=0.0014580488).

BP6

Variant 4-23813084-G-A is Benign according to our data. Variant chr4-23813084-G-A is described in ClinVar as [Benign]. Clinvar id is 3056132.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 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.1835C>T	p.Thr612Met	missense_variant	9/13	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.1835C>T	p.Thr612Met	missense_variant	9/13	1	NM_013261.5	ENSP00000264867	P1	Q9UBK2-1
PPARGC1A	ENST00000613098.4 linkuse as main transcript	c.1454C>T	p.Thr485Met	missense_variant	8/12	1		ENSP00000481498		Q9UBK2-9
PPARGC1A	ENST00000506055.5 linkuse as main transcript	c.*1050C>T		3_prime_UTR_variant, NMD_transcript_variant	9/13	1		ENSP00000423075		Q9UBK2-2
PPARGC1A	ENST00000509702.5 linkuse as main transcript	n.1875C>T		non_coding_transcript_exon_variant	9/15	5

Frequencies

GnomAD3 genomes

AF:

0.0726

AC:

11040

AN:

152076

Hom.:

458

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0631

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0855

Gnomad ASJ

AF:

0.0809

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.104

Gnomad MID

AF:

0.0732

Gnomad NFE

AF:

0.0558

Gnomad OTH

AF:

0.0798

GnomAD3 exomes

AF:

0.0860

AC:

21604

AN:

251286

Hom.:

1170

AF XY:

0.0873

AC XY:

11852

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.0592

Gnomad AMR exome

AF:

0.0992

Gnomad ASJ exome

AF:

0.0852

Gnomad EAS exome

AF:

0.183

Gnomad SAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.0549

Gnomad OTH exome

AF:

0.0850

GnomAD4 exome

AF:

0.0649

AC:

94876

AN:

1461668

Hom.:

4021

Cov.:

AF XY:

0.0668

AC XY:

48598

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0616

Gnomad4 AMR exome

AF:

0.0973

Gnomad4 ASJ exome

AF:

0.0830

Gnomad4 EAS exome

AF:

0.194

Gnomad4 SAS exome

AF:

0.127

Gnomad4 FIN exome

AF:

0.104

Gnomad4 NFE exome

AF:

0.0516

Gnomad4 OTH exome

AF:

0.0715

GnomAD4 genome

AF:

0.0725

AC:

11040

AN:

152194

Hom.:

458

Cov.:

AF XY:

0.0779

AC XY:

5792

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0629

Gnomad4 AMR

AF:

0.0856

Gnomad4 ASJ

AF:

0.0809

Gnomad4 EAS

AF:

0.183

Gnomad4 SAS

AF:

0.145

Gnomad4 FIN

AF:

0.104

Gnomad4 NFE

AF:

0.0558

Gnomad4 OTH

AF:

0.0784

Alfa

AF:

0.0603

Hom.:

664

Bravo

AF:

0.0689

TwinsUK

AF:

0.0547

AC:

203

ALSPAC

AF:

0.0514

AC:

198

ESP6500AA

AF:

0.0620

AC:

273

ESP6500EA

AF:

0.0545

AC:

469

ExAC

AF:

0.0828

AC:

10050

Asia WGS

AF:

0.141

AC:

487

AN:

3478

EpiCase

AF:

0.0636

EpiControl

AF:

0.0609

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

Feb 22, 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

0.096

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.12

Sift

Uncertain

0.028

D;.

Sift4G

Uncertain

0.019

D;D

Polyphen

0.0

B;.

Vest4

0.11

MPC

0.22

ClinPred

0.0015

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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