dbSNP rs2932976: PPARGC1A:c.877+3575C>T (chr4-23820705-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

The NM_013261.5(PPARGC1A):c.877+3575C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 347,638 control chromosomes in the GnomAD database, including 11,521 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 0.22 ( 4457 hom., cov: 32)

Exomes 𝑓: 0.25 ( 7064 hom. )

Consequence

PPARGC1A
NM_013261.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.36

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.17).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5 link	c.877+3575C>T		intron_variant	Intron 7 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.877+3575C>T		intron_variant	Intron 7 of 12	1	NM_013261.5	ENSP00000264867.2		Q9UBK2-1

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33536

AN:

151892

Hom.:

4457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.288

Gnomad AMR

AF:

0.325

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.0834

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.335

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.264

Gnomad OTH

AF:

0.209

GnomAD4 exome

AF:

0.254

AC:

49605

AN:

195626

Hom.:

7064

AF XY:

0.247

AC XY:

28281

AN XY:

114416

show subpopulations

African (AFR)

AF:

0.103

AC:

480

AN:

4640

American (AMR)

AF:

0.426

AC:

6819

AN:

16018

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

1269

AN:

7068

East Asian (EAS)

AF:

0.0785

AC:

417

AN:

5312

South Asian (SAS)

AF:

0.215

AC:

8964

AN:

41628

European-Finnish (FIN)

AF:

0.315

AC:

2917

AN:

9248

Middle Eastern (MID)

AF:

0.179

AC:

416

AN:

2324

European-Non Finnish (NFE)

AF:

0.262

AC:

26309

AN:

100404

Other (OTH)

AF:

0.224

AC:

2014

AN:

8984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1599

3198

4798

6397

7996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<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:

0.221

AC:

33557

AN:

152012

Hom.:

4457

Cov.:

AF XY:

0.225

AC XY:

16721

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.104

AC:

4312

AN:

41506

American (AMR)

AF:

0.325

AC:

4961

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

620

AN:

3468

East Asian (EAS)

AF:

0.0828

AC:

428

AN:

5166

South Asian (SAS)

AF:

0.208

AC:

1001

AN:

4818

European-Finnish (FIN)

AF:

0.335

AC:

3531

AN:

10544

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.264

AC:

17944

AN:

67936

Other (OTH)

AF:

0.212

AC:

448

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1279

2558

3838

5117

6396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.241

Hom.:

7719

Bravo

AF:

0.212

Asia WGS

AF:

0.174

AC:

605

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

1.4

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over