Genetic Variant PPARGC1A:c.54+945A>G (chr4-23888959-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_013261.5(PPARGC1A):c.54+945A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 984,754 control chromosomes in the GnomAD database, including 159,756 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.59 ( 26913 hom., cov: 31)

Exomes 𝑓: 0.56 ( 132843 hom. )

Consequence

PPARGC1A
NM_013261.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.592

Publications

10 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=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5 link	c.54+945A>G		intron_variant	Intron 1 of 12	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.54+945A>G		intron_variant	Intron 1 of 12	1	NM_013261.5	ENSP00000264867.2		Q9UBK2-1

Frequencies

GnomAD3 genomes

AF:

0.589

AC:

89431

AN:

151790

Hom.:

26880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.700

Gnomad AMI

AF:

0.558

Gnomad AMR

AF:

0.567

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.584

Gnomad SAS

AF:

0.577

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.610

GnomAD4 exome

AF:

0.564

AC:

469709

AN:

832846

Hom.:

132843

Cov.:

AF XY:

0.564

AC XY:

217020

AN XY:

384620

show subpopulations

African (AFR)

AF:

0.721

AC:

11371

AN:

15780

American (AMR)

AF:

0.529

AC:

521

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.607

AC:

3129

AN:

5152

East Asian (EAS)

AF:

0.603

AC:

2190

AN:

3630

South Asian (SAS)

AF:

0.559

AC:

9200

AN:

16456

European-Finnish (FIN)

AF:

0.478

AC:

132

AN:

276

Middle Eastern (MID)

AF:

0.664

AC:

1076

AN:

1620

European-Non Finnish (NFE)

AF:

0.559

AC:

426138

AN:

761664

Other (OTH)

AF:

0.585

AC:

15952

AN:

27284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

10713

21426

32138

42851

53564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16380

32760

49140

65520

81900

<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:

0.589

AC:

89506

AN:

151908

Hom.:

26913

Cov.:

AF XY:

0.583

AC XY:

43278

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.700

AC:

29004

AN:

41412

American (AMR)

AF:

0.567

AC:

8650

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

2131

AN:

3470

East Asian (EAS)

AF:

0.583

AC:

2994

AN:

5134

South Asian (SAS)

AF:

0.578

AC:

2779

AN:

4810

European-Finnish (FIN)

AF:

0.406

AC:

4283

AN:

10538

Middle Eastern (MID)

AF:

0.704

AC:

207

AN:

294

European-Non Finnish (NFE)

AF:

0.554

AC:

37671

AN:

67968

Other (OTH)

AF:

0.606

AC:

1278

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1841

3682

5522

7363

9204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<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:

0.591

Hom.:

12872

Bravo

AF:

0.610

Asia WGS

AF:

0.577

AC:

2008

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

-0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Computational scores

Splicing

Publications

Other links and lift over