rs17574213

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_013261.5(PPARGC1A):c.1425C>T(p.Asp475=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,884 control chromosomes in the GnomAD database, including 3,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.051 ( 229 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3677 hom. )

Consequence

PPARGC1A
NM_013261.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.565

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 made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 4-23814058-G-A is Benign according to our data. Variant chr4-23814058-G-A is described in ClinVar as [Benign]. Clinvar id is 3037609.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.565 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5 linkuse as main transcript	c.1425C>T	p.Asp475=	synonymous_variant	8/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7 linkuse as main transcript	c.1425C>T	p.Asp475=	synonymous_variant	8/13	1	NM_013261.5	P1	Q9UBK2-1
PPARGC1A	ENST00000613098.4 linkuse as main transcript	c.1044C>T	p.Asp348=	synonymous_variant	7/12	1			Q9UBK2-9
PPARGC1A	ENST00000506055.5 linkuse as main transcript	c.*640C>T		3_prime_UTR_variant, NMD_transcript_variant	8/13	1			Q9UBK2-2
PPARGC1A	ENST00000509702.5 linkuse as main transcript	n.1465C>T		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7773

AN:

152010

Hom.:

229

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0437

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0333

Gnomad FIN

AF:

0.0699

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0693

Gnomad OTH

AF:

0.0340

GnomAD3 exomes

AF:

0.0493

AC:

12361

AN:

250682

Hom.:

355

AF XY:

0.0495

AC XY:

6708

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.0297

Gnomad AMR exome

AF:

0.0375

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.0339

Gnomad FIN exome

AF:

0.0689

Gnomad NFE exome

AF:

0.0659

Gnomad OTH exome

AF:

0.0506

GnomAD4 exome

AF:

0.0657

AC:

96056

AN:

1461756

Hom.:

3677

Cov.:

AF XY:

0.0641

AC XY:

46627

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0293

Gnomad4 AMR exome

AF:

0.0388

Gnomad4 ASJ exome

AF:

0.0280

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.0353

Gnomad4 FIN exome

AF:

0.0695

Gnomad4 NFE exome

AF:

0.0740

Gnomad4 OTH exome

AF:

0.0563

GnomAD4 genome

AF:

0.0511

AC:

7775

AN:

152128

Hom.:

229

Cov.:

AF XY:

0.0497

AC XY:

3696

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0288

Gnomad4 AMR

AF:

0.0436

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0337

Gnomad4 FIN

AF:

0.0699

Gnomad4 NFE

AF:

0.0693

Gnomad4 OTH

AF:

0.0337

Alfa

AF:

0.0594

Hom.:

219

Bravo

AF:

0.0494

Asia WGS

AF:

0.0140

AC:

AN:

3476

EpiCase

AF:

0.0613

EpiControl

AF:

0.0613

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PPARGC1A-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

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

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over