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rs8192678

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_013261.5(PPARGC1A):c.1444G>A(p.Gly482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,613,718 control chromosomes in the GnomAD database, including 88,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.26 ( 6219 hom., cov: 32)
Exomes 𝑓: 0.33 ( 82752 hom. )

Consequence

PPARGC1A
NM_013261.5 missense

Scores

18

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.21
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0026910305).
BP6
Variant 4-23814039-C-T is Benign according to our data. Variant chr4-23814039-C-T is described in ClinVar as [Benign]. Clinvar id is 3060597.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPARGC1ANM_013261.5 linkuse as main transcriptc.1444G>A p.Gly482Ser missense_variant 8/13 ENST00000264867.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPARGC1AENST00000264867.7 linkuse as main transcriptc.1444G>A p.Gly482Ser missense_variant 8/131 NM_013261.5 P1Q9UBK2-1
PPARGC1AENST00000613098.4 linkuse as main transcriptc.1063G>A p.Gly355Ser missense_variant 7/121 Q9UBK2-9
PPARGC1AENST00000506055.5 linkuse as main transcriptc.*659G>A 3_prime_UTR_variant, NMD_transcript_variant 8/131 Q9UBK2-2
PPARGC1AENST00000509702.5 linkuse as main transcriptn.1484G>A non_coding_transcript_exon_variant 8/155

Frequencies

GnomAD3 genomes
AF:
0.263
AC:
39997
AN:
151906
Hom.:
6228
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0949
Gnomad AMI
AF:
0.188
Gnomad AMR
AF:
0.292
Gnomad ASJ
AF:
0.365
Gnomad EAS
AF:
0.428
Gnomad SAS
AF:
0.267
Gnomad FIN
AF:
0.299
Gnomad MID
AF:
0.328
Gnomad NFE
AF:
0.335
Gnomad OTH
AF:
0.306
GnomAD3 exomes
AF:
0.309
AC:
77425
AN:
250648
Hom.:
12728
AF XY:
0.314
AC XY:
42497
AN XY:
135426
show subpopulations
Gnomad AFR exome
AF:
0.0864
Gnomad AMR exome
AF:
0.261
Gnomad ASJ exome
AF:
0.368
Gnomad EAS exome
AF:
0.426
Gnomad SAS exome
AF:
0.268
Gnomad FIN exome
AF:
0.298
Gnomad NFE exome
AF:
0.344
Gnomad OTH exome
AF:
0.320
GnomAD4 exome
AF:
0.331
AC:
484463
AN:
1461694
Hom.:
82752
Cov.:
55
AF XY:
0.330
AC XY:
240299
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.0832
Gnomad4 AMR exome
AF:
0.264
Gnomad4 ASJ exome
AF:
0.366
Gnomad4 EAS exome
AF:
0.446
Gnomad4 SAS exome
AF:
0.268
Gnomad4 FIN exome
AF:
0.304
Gnomad4 NFE exome
AF:
0.343
Gnomad4 OTH exome
AF:
0.325
GnomAD4 genome
AF:
0.263
AC:
39981
AN:
152024
Hom.:
6219
Cov.:
32
AF XY:
0.262
AC XY:
19498
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.0945
Gnomad4 AMR
AF:
0.292
Gnomad4 ASJ
AF:
0.365
Gnomad4 EAS
AF:
0.428
Gnomad4 SAS
AF:
0.267
Gnomad4 FIN
AF:
0.299
Gnomad4 NFE
AF:
0.335
Gnomad4 OTH
AF:
0.303
Alfa
AF:
0.323
Hom.:
15477
Bravo
AF:
0.260
TwinsUK
AF:
0.353
AC:
1310
ALSPAC
AF:
0.351
AC:
1352
ESP6500AA
AF:
0.103
AC:
455
ESP6500EA
AF:
0.347
AC:
2988
ExAC
AF:
0.308
AC:
37387
Asia WGS
AF:
0.329
AC:
1145
AN:
3478
EpiCase
AF:
0.344
EpiControl
AF:
0.353

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

PPARGC1A-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 17, 2019This 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
0.056
BayesDel_addAF
Benign
-0.79
T
BayesDel_noAF
Benign
-0.77
Cadd
Benign
16
Dann
Benign
0.38
DEOGEN2
Benign
0.21
T;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.58
T;T
MetaRNN
Benign
0.0027
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.3
N;.
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.47
T
PROVEAN
Benign
1.0
N;.
REVEL
Benign
0.10
Sift
Benign
1.0
T;.
Sift4G
Benign
0.85
T;T
Polyphen
0.053
B;.
Vest4
0.041
MPC
0.22
ClinPred
0.0068
T
GERP RS
6.0
Varity_R
0.030
gMVP
0.096

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.

Other links and lift over

dbSNP: rs8192678; hg19: chr4-23815662; COSMIC: COSV53527108; COSMIC: COSV53527108; API