4-23813787-G-A

Position:

• chr4-23813787-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_013261.5(PPARGC1A):​c.1696C>T​(p.Arg566Cys) 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 1,612,860 control chromosomes in the GnomAD database, including 34 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 0.0076 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.83

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005928457).
• BP6: Variant 4-23813787-G-A is Benign according to our data. Variant chr4-23813787-G-A is described in ClinVar as [Benign]. Clinvar id is 778140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00755 (1150/152222) while in subpopulation AFR AF= 0.0236 (982/41550). AF 95% confidence interval is 0.0224. There are 11 homozygotes in gnomad4. There are 573 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.1696C>T	p.Arg566Cys	missense_variant	8/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1696C>T	p.Arg566Cys	missense_variant	8/13	1	NM_013261.5	P1
PPARGC1A	ENST00000613098.4	c.1315C>T	p.Arg439Cys	missense_variant	7/12	1
PPARGC1A	ENST00000506055.5	c.*911C>T		3_prime_UTR_variant, NMD_transcript_variant	8/13	1
PPARGC1A	ENST00000509702.5	n.1736C>T		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes AF: 0.00755 AC: 1148 AN: 152104 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00240 AC: 602 AN: 251156 Hom.: 9 AF XY: 0.00213 AC XY: 289 AN XY: 135712

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00114 AC: 1660 AN: 1460638 Hom.: 23 Cov.: 30 AF XY: 0.00109 AC XY: 791 AN XY: 726720

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.00302

GnomAD4 genome AF: 0.00755 AC: 1150 AN: 152222 Hom.: 11 Cov.: 33 AF XY: 0.00770 AC XY: 573 AN XY: 74418

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00694

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00912

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00261 AC: 317

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	0.056
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.12
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.23	T;T
Polyphen		0.0010	B;.
Vest4		0.20
MVP		0.43
MPC		0.29
ClinPred		0.018	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.42

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: rs58772979; hg19: chr4-23815410; COSMIC: COSV53532626; COSMIC: COSV53532626;