rs3736265

Positions:

• chr4-23813084-G-A
• chr4-23813084-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_013261.5(PPARGC1A):​c.1835C>T​(p.Thr612Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 1,613,862 control chromosomes in the GnomAD database, including 4,479 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 Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.073 (458 hom., cov: 31)
  • Exomes 𝑓: 0.065 (4021 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.51

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014580488).
• BP6: Variant 4-23813084-G-A is Benign according to our data. Variant chr4-23813084-G-A is described in ClinVar as [Benign]. Clinvar id is 3056132.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.1835C>T	p.Thr612Met	missense_variant	9/13	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1835C>T	p.Thr612Met	missense_variant	9/13	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11040 AN: 152076 Hom.: 458 Cov.: 31

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0798

GnomAD3 exomes AF: 0.0860 AC: 21604 AN: 251286 Hom.: 1170 AF XY: 0.0873 AC XY: 11852 AN XY: 135790

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.0992

Gnomad ASJ exome AF: 0.0852

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0850

GnomAD4 exome AF: 0.0649 AC: 94876 AN: 1461668 Hom.: 4021 Cov.: 32 AF XY: 0.0668 AC XY: 48598 AN XY: 727152

Gnomad4 AFR exome AF: 0.0616

Gnomad4 AMR exome AF: 0.0973

Gnomad4 ASJ exome AF: 0.0830

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0516

Gnomad4 OTH exome AF: 0.0715

GnomAD4 genome AF: 0.0725 AC: 11040 AN: 152194 Hom.: 458 Cov.: 31 AF XY: 0.0779 AC XY: 5792 AN XY: 74398

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.0856

Gnomad4 ASJ AF: 0.0809

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0558

Gnomad4 OTH AF: 0.0784

Alfa AF: 0.0603 Hom.: 664

Bravo AF: 0.0689

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0514 AC: 198

ESP6500AA AF: 0.0620 AC: 273

ESP6500EA AF: 0.0545 AC: 469

ExAC AF: 0.0828 AC: 10050

Asia WGS AF: 0.141 AC: 487 AN: 3478

EpiCase AF: 0.0636

EpiControl AF: 0.0609

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPARGC1A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 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	0.096
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.12
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.019	D;D
Polyphen		0.0	B;.
Vest4		0.11
MPC		0.22
ClinPred		0.0015	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.26

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

Other links and lift over

dbSNP: rs3736265; hg19: chr4-23814707; COSMIC: COSV53525186; COSMIC: COSV53525186;