Genetic Variant NM_013261.5:c.1584G>A (chr4-23813899-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_013261.5(PPARGC1A):c.1584G>A(p.Thr528Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,613,140 control chromosomes in the GnomAD database, including 122,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.34 ( 9525 hom., cov: 32)

Exomes 𝑓: 0.39 ( 113384 hom. )

Consequence

PPARGC1A
NM_013261.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.85

Publications

47 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 4-23813899-C-T is Benign according to our data. Variant chr4-23813899-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060606.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=1.85 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 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.1584G>A	p.Thr528Thr	synonymous	Exon 8 of 13	NP_037393.1
PPARGC1A	NM_001330751.2		c.1599G>A	p.Thr533Thr	synonymous	Exon 10 of 15	NP_001317680.1
PPARGC1A	NM_001354825.2		c.1599G>A	p.Thr533Thr	synonymous	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.1584G>A	p.Thr528Thr	synonymous	Exon 8 of 13	ENSP00000264867.2
PPARGC1A	ENST00000613098.4	TSL:1	c.1203G>A	p.Thr401Thr	synonymous	Exon 7 of 12	ENSP00000481498.1
PPARGC1A	ENST00000506055.5	TSL:1	n.*799G>A		non_coding_transcript_exon	Exon 8 of 13	ENSP00000423075.1

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52349

AN:

151850

Hom.:

9532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.310

Gnomad AMR

AF:

0.360

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.330

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.393

Gnomad OTH

AF:

0.388

GnomAD2 exomes

AF:

0.370

AC:

92700

AN:

250224

AF XY:

0.375

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.323

Gnomad ASJ exome

AF:

0.484

Gnomad EAS exome

AF:

0.427

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.403

Gnomad OTH exome

AF:

0.397

GnomAD4 exome

AF:

0.391

AC:

571111

AN:

1461172

Hom.:

113384

Cov.:

AF XY:

0.390

AC XY:

283561

AN XY:

726890

show subpopulations

African (AFR)

AF:

0.234

AC:

7829

AN:

33462

American (AMR)

AF:

0.327

AC:

14639

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

12475

AN:

26128

East Asian (EAS)

AF:

0.447

AC:

17724

AN:

39692

South Asian (SAS)

AF:

0.328

AC:

28301

AN:

86228

European-Finnish (FIN)

AF:

0.340

AC:

18168

AN:

53398

Middle Eastern (MID)

AF:

0.451

AC:

2600

AN:

5760

European-Non Finnish (NFE)

AF:

0.401

AC:

445601

AN:

1111416

Other (OTH)

AF:

0.394

AC:

23774

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

20925

41850

62774

83699

104624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13828

27656

41484

55312

69140

<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:

0.344

AC:

52345

AN:

151968

Hom.:

9525

Cov.:

AF XY:

0.342

AC XY:

25414

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.240

AC:

9960

AN:

41454

American (AMR)

AF:

0.360

AC:

5492

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

1658

AN:

3468

East Asian (EAS)

AF:

0.430

AC:

2215

AN:

5146

South Asian (SAS)

AF:

0.330

AC:

1585

AN:

4806

European-Finnish (FIN)

AF:

0.332

AC:

3514

AN:

10578

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.393

AC:

26697

AN:

67936

Other (OTH)

AF:

0.383

AC:

808

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1717

3434

5150

6867

8584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.384

Hom.:

21779

Bravo

AF:

0.347

Asia WGS

AF:

0.376

AC:

1310

AN:

3478

EpiCase

AF:

0.409

EpiControl

AF:

0.417

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PPARGC1A-related disorder

Benign:1

Oct 18, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over