4-23813087-C-T

Position:

chr4-23813087-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_013261.5(PPARGC1A):c.1832G>A(p.Arg611His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,996 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

PPARGC1A
NM_013261.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.781

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:

PPARGC1A (HGNC:):

PPARGC1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025871992).

BP6

Variant 4-23813087-C-T is Benign according to our data. Variant chr4-23813087-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 388 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARGC1A	NM_013261.5 linkuse as main transcript	c.1832G>A	p.Arg611His	missense_variant	9/13	ENST00000264867.7	NP_037393.1	Q9UBK2-1A0A024R9Q9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7 linkuse as main transcript	c.1832G>A	p.Arg611His	missense_variant	9/13	1	NM_013261.5	ENSP00000264867.2		Q9UBK2-1

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

388

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00328

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00241

AC:

606

AN:

251260

Hom.:

AF XY:

0.00248

AC XY:

337

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00166

AC:

2426

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1231

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.00147

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.00255

AC:

388

AN:

152210

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

217

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.00328

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00234

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00229

AC:

278

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00175

EpiControl

AF:

0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PPARGC1A: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 21, 2018	- -

PPARGC1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 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

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.11

Sift

Uncertain

0.028

D;.

Sift4G

Benign

0.083

T;T

Polyphen

0.0

B;.

Vest4

0.28

MVP

0.41

MPC

0.27

ClinPred

0.019

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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