NM_013261.5:c.1444G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

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

Publications

403 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=0.0026910305).

BP6

Variant 4-23814039-C-T is Benign according to our data. Variant chr4-23814039-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PPARGC1A	NM_013261.5	MANE Select	c.1444G>A	p.Gly482Ser	missense	Exon 8 of 13	NP_037393.1
PPARGC1A	NM_001330751.2		c.1459G>A	p.Gly487Ser	missense	Exon 10 of 15	NP_001317680.1
PPARGC1A	NM_001354825.2		c.1459G>A	p.Gly487Ser	missense	Exon 9 of 14	NP_001341754.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.1444G>A	p.Gly482Ser	missense	Exon 8 of 13	ENSP00000264867.2
PPARGC1A	ENST00000613098.4	TSL:1	c.1063G>A	p.Gly355Ser	missense	Exon 7 of 12	ENSP00000481498.1
PPARGC1A	ENST00000506055.5	TSL:1	n.*659G>A		non_coding_transcript_exon	Exon 8 of 13	ENSP00000423075.1

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

GnomAD2 exomes

AF:

0.309

AC:

77425

AN:

250648

AF XY:

0.314

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 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

African (AFR)

AF:

0.0832

AC:

2784

AN:

33470

American (AMR)

AF:

0.264

AC:

11814

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

9562

AN:

26130

East Asian (EAS)

AF:

0.446

AC:

17709

AN:

39698

South Asian (SAS)

AF:

0.268

AC:

23128

AN:

86256

European-Finnish (FIN)

AF:

0.304

AC:

16232

AN:

53418

Middle Eastern (MID)

AF:

0.327

AC:

1886

AN:

5768

European-Non Finnish (NFE)

AF:

0.343

AC:

381745

AN:

1111858

Other (OTH)

AF:

0.325

AC:

19603

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

20219

40438

60656

80875

101094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12234

24468

36702

48936

61170

<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:

0.263

AC:

39981

AN:

152024

Hom.:

6219

Cov.:

AF XY:

0.262

AC XY:

19498

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0945

AC:

3924

AN:

41508

American (AMR)

AF:

0.292

AC:

4456

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

1265

AN:

3470

East Asian (EAS)

AF:

0.428

AC:

2204

AN:

5148

South Asian (SAS)

AF:

0.267

AC:

1285

AN:

4812

European-Finnish (FIN)

AF:

0.299

AC:

3156

AN:

10554

Middle Eastern (MID)

AF:

0.318

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.335

AC:

22787

AN:

67948

Other (OTH)

AF:

0.303

AC:

640

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1426

2852

4279

5705

7131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.317

Hom.:

31354

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

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PPARGC1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.21

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

PhyloP100

2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

1.0

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Benign

0.85

Polyphen

0.053

Vest4

0.041

MPC

0.22

ClinPred

0.0068

GERP RS

6.0

Varity_R

0.030

gMVP

0.096

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over