4-23814255-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013261.5(PPARGC1A):c.1228C>A(p.Leu410Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,034 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (18 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.61

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041254163).
• BP6: Variant 4-23814255-G-T is Benign according to our data. Variant chr4-23814255-G-T is described in ClinVar as [Benign]. Clinvar id is 788779.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 = 0.00574 (874/152204) while in subpopulation AFR AF= 0.0195 (809/41530). AF 95% confidence interval is 0.0184. There are 9 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 869 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.1228C>A	p.Leu410Ile	missense_variant	8/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1228C>A	p.Leu410Ile	missense_variant	8/13	1	NM_013261.5	P1
PPARGC1A	ENST00000613098.4	c.847C>A	p.Leu283Ile	missense_variant	7/12	1
PPARGC1A	ENST00000506055.5	c.*443C>A		3_prime_UTR_variant, NMD_transcript_variant	8/13	1
PPARGC1A	ENST00000509702.5	n.1268C>A		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152086 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00177 AC: 445 AN: 250828 Hom.: 1 AF XY: 0.00147 AC XY: 199 AN XY: 135542

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000867 AC: 1268 AN: 1461830 Hom.: 18 Cov.: 70 AF XY: 0.000814 AC XY: 592 AN XY: 727220

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152204 Hom.: 9 Cov.: 32 AF XY: 0.00554 AC XY: 412 AN XY: 74402

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00657

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00196 AC: 238

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PPARGC1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 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

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.16	N;.
REVEL	Benign	0.20
Sift	Benign	0.12	T;.
Sift4G	Benign	0.43	T;T
Polyphen		0.73	P;.
Vest4		0.15
MVP		0.40
MPC		0.24
ClinPred		0.041	T
GERP RS		6.2
Varity_R		0.13
gMVP		0.051

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

Other links and lift over

dbSNP: rs34514918; hg19: chr4-23815878;