chr4-23813087-C-T

Position:

• chr4-23813087-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013261.5(PPARGC1A):​c.1832G>A​(p.Arg611His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,996 control chromosomes in the GnomAD database, including 6 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.781

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025871992).
• BP6: Variant 4-23813087-C-T is Benign according to our data. Variant chr4-23813087-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 388 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.1832G>A	p.Arg611His	missense_variant	9/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1832G>A	p.Arg611His	missense_variant	9/13	1	NM_013261.5	P1
PPARGC1A	ENST00000613098.4	c.1451G>A	p.Arg484His	missense_variant	8/12	1
PPARGC1A	ENST00000506055.5	c.*1047G>A		3_prime_UTR_variant, NMD_transcript_variant	9/13	1
PPARGC1A	ENST00000509702.5	n.1872G>A		non_coding_transcript_exon_variant	9/15	5

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00241 AC: 606 AN: 251260 Hom.: 2 AF XY: 0.00248 AC XY: 337 AN XY: 135784

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00166 AC: 2426 AN: 1461786 Hom.: 5 Cov.: 32 AF XY: 0.00169 AC XY: 1231 AN XY: 727204

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152210 Hom.: 1 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74424

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00234 Hom.: 1

Bravo AF: 0.00124

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	PPARGC1A: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 21, 2018	- -

PPARGC1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 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	0.088
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.11
Sift	Uncertain	0.028	D;.
Sift4G	Benign	0.083	T;T
Polyphen		0.0	B;.
Vest4		0.28
MVP		0.41
MPC		0.27
ClinPred		0.019	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144103777; hg19: chr4-23814710; COSMIC: COSV53531783; COSMIC: COSV53531783;