4-23813899-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_013261.5(PPARGC1A):c.1584G>A(p.Thr528=) 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 (★).

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 criteria provided, single submitter B:1

Conservation

PhyloP100: 1.85

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 -13 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 id is 3060606.Status of the report is criteria_provided_single_submitter, 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5 linkuse as main transcript	c.1584G>A	p.Thr528=	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.1584G>A	p.Thr528=	synonymous_variant	8/13	1	NM_013261.5	P1	Q9UBK2-1
PPARGC1A	ENST00000613098.4 linkuse as main transcript	c.1203G>A	p.Thr401=	synonymous_variant	7/12	1			Q9UBK2-9
PPARGC1A	ENST00000506055.5 linkuse as main transcript	c.*799G>A		3_prime_UTR_variant, NMD_transcript_variant	8/13	1			Q9UBK2-2
PPARGC1A	ENST00000509702.5 linkuse as main transcript	n.1624G>A		non_coding_transcript_exon_variant	8/15	5

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

GnomAD3 exomes

AF:

0.370

AC:

92700

AN:

250224

Hom.:

17599

AF XY:

0.375

AC XY:

50647

AN XY:

135204

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 SAS exome

AF:

0.328

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

Gnomad4 AFR exome

AF:

0.234

Gnomad4 AMR exome

AF:

0.327

Gnomad4 ASJ exome

AF:

0.477

Gnomad4 EAS exome

AF:

0.447

Gnomad4 SAS exome

AF:

0.328

Gnomad4 FIN exome

AF:

0.340

Gnomad4 NFE exome

AF:

0.401

Gnomad4 OTH exome

AF:

0.394

GnomAD4 genome

AF:

0.344

AC:

52345

AN:

151968

Hom.:

9525

Cov.:

AF XY:

0.342

AC XY:

25414

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.240

Gnomad4 AMR

AF:

0.360

Gnomad4 ASJ

AF:

0.478

Gnomad4 EAS

AF:

0.430

Gnomad4 SAS

AF:

0.330

Gnomad4 FIN

AF:

0.332

Gnomad4 NFE

AF:

0.393

Gnomad4 OTH

AF:

0.383

Alfa

AF:

0.386

Hom.:

16301

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: 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

Oct 18, 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

-0.38

Cadd

Benign

Dann

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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