4-23814039-C-T

Variant names:

• chr4-23814039-C-T
• rs8192678
• NM_013261.5:c.1444G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.26 (6219 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82752 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.21
• Publications: 403 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3060597.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.1444G>A	p.Gly482Ser	missense_variant	Exon 8 of 13	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1444G>A	p.Gly482Ser	missense_variant	Exon 8 of 13	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39997 AN: 151906 Hom.: 6228 Cov.: 32

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

GnomAD2 exomes AF: 0.309 AC: 77425 AN: 250648 AF XY: 0.314

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 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

African (AFR) AF: 0.0832 AC: 2784 AN: 33470

American (AMR) AF: 0.264 AC: 11814 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9562 AN: 26130

East Asian (EAS) AF: 0.446 AC: 17709 AN: 39698

South Asian (SAS) AF: 0.268 AC: 23128 AN: 86256

European-Finnish (FIN) AF: 0.304 AC: 16232 AN: 53418

Middle Eastern (MID) AF: 0.327 AC: 1886 AN: 5768

European-Non Finnish (NFE) AF: 0.343 AC: 381745 AN: 1111858

Other (OTH) AF: 0.325 AC: 19603 AN: 60382

GnomAD4 genome AF: 0.263 AC: 39981 AN: 152024 Hom.: 6219 Cov.: 32 AF XY: 0.262 AC XY: 19498 AN XY: 74282

African (AFR) AF: 0.0945 AC: 3924 AN: 41508

American (AMR) AF: 0.292 AC: 4456 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3470

East Asian (EAS) AF: 0.428 AC: 2204 AN: 5148

South Asian (SAS) AF: 0.267 AC: 1285 AN: 4812

European-Finnish (FIN) AF: 0.299 AC: 3156 AN: 10554

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.335 AC: 22787 AN: 67948

Other (OTH) AF: 0.303 AC: 640 AN: 2112

Alfa AF: 0.317 Hom.: 31354

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: no assertion criteria provided

Submissions by phenotype

PPARGC1A-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.056
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;.
PhyloP100		2.2
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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