rs3736265

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_013261.5(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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T612P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.073 ( 458 hom., cov: 31)

Exomes 𝑓: 0.065 ( 4021 hom. )

Consequence

PPARGC1A
NM_013261.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.51

Publications

72 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5 link	c.1835C>T	p.Thr612Met	missense_variant	Exon 9 of 13	ENST00000264867.7	NP_037393.1	Q9UBK2-1A0A024R9Q9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7 link	c.1835C>T	p.Thr612Met	missense_variant	Exon 9 of 13	1	NM_013261.5	ENSP00000264867.2		Q9UBK2-1

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

GnomAD2 exomes

AF:

0.0860

AC:

21604

AN:

251286

AF XY:

0.0873

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 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

African (AFR)

AF:

0.0616

AC:

2063

AN:

33472

American (AMR)

AF:

0.0973

AC:

4350

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0830

AC:

2169

AN:

26128

East Asian (EAS)

AF:

0.194

AC:

7682

AN:

39694

South Asian (SAS)

AF:

0.127

AC:

10951

AN:

86246

European-Finnish (FIN)

AF:

0.104

AC:

5559

AN:

53414

Middle Eastern (MID)

AF:

0.0636

AC:

367

AN:

5768

European-Non Finnish (NFE)

AF:

0.0516

AC:

57418

AN:

1111836

Other (OTH)

AF:

0.0715

AC:

4317

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

4871

9741

14612

19482

24353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2306

4612

6918

9224

11530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0725

AC:

11040

AN:

152194

Hom.:

458

Cov.:

AF XY:

0.0779

AC XY:

5792

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0629

AC:

2611

AN:

41524

American (AMR)

AF:

0.0856

AC:

1310

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0809

AC:

281

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

946

AN:

5156

South Asian (SAS)

AF:

0.145

AC:

697

AN:

4808

European-Finnish (FIN)

AF:

0.104

AC:

1105

AN:

10596

Middle Eastern (MID)

AF:

0.0753

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0558

AC:

3793

AN:

68020

Other (OTH)

AF:

0.0784

AC:

166

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

512

1023

1535

2046

2558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0609

Hom.:

1302

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

Feb 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

1.5

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over