4-23814170-A-G

Position:

chr4-23814170-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013261.5(PPARGC1A):c.1313T>C(p.Leu438Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,092 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 24 hom. )

Consequence

PPARGC1A
NM_013261.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.138

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014434755).

BP6

Variant 4-23814170-A-G is Benign according to our data. Variant chr4-23814170-A-G is described in ClinVar as [Benign]. Clinvar id is 778141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00772 (1176/152246) while in subpopulation AFR AF= 0.0244 (1014/41538). AF 95% confidence interval is 0.0232. There are 12 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5 linkuse as main transcript	c.1313T>C	p.Leu438Ser	missense_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.1313T>C	p.Leu438Ser	missense_variant	8/13	1	NM_013261.5	P1	Q9UBK2-1
PPARGC1A	ENST00000613098.4 linkuse as main transcript	c.932T>C	p.Leu311Ser	missense_variant	7/12	1			Q9UBK2-9
PPARGC1A	ENST00000506055.5 linkuse as main transcript	c.*528T>C		3_prime_UTR_variant, NMD_transcript_variant	8/13	1			Q9UBK2-2
PPARGC1A	ENST00000509702.5 linkuse as main transcript	n.1353T>C		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes

AF:

0.00771

AC:

1173

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00236

AC:

592

AN:

250894

Hom.:

AF XY:

0.00209

AC XY:

284

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0254

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000362

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00109

AC:

1594

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

761

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0287

Gnomad4 AMR exome

AF:

0.00315

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000172

Gnomad4 OTH exome

AF:

0.00321

GnomAD4 genome

AF:

0.00772

AC:

1176

AN:

152246

Hom.:

Cov.:

AF XY:

0.00786

AC XY:

585

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.00681

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00160

Hom.:

Bravo

AF:

0.00923

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0213

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PPARGC1A-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.39

DANN

Benign

0.40

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

0.51

N;.

REVEL

Benign

0.083

Sift

Benign

0.73

T;.

Sift4G

Benign

0.74

T;T

Polyphen

0.013

B;.

Vest4

0.065

MVP

0.13

MPC

0.31

ClinPred

0.0044

GERP RS

-8.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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