4-23813899-C-T

Variant names:

• chr4-23813899-C-T
• rs3755863
• NM_013261.5:c.1584G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_013261.5(PPARGC1A):​c.1584G>A​(p.Thr528Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,613,140 control chromosomes in the GnomAD database, including 122,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.34 (9525 hom., cov: 32)
  • Exomes 𝑓: 0.39 (113384 hom.)
• Consequence: PPARGC1A NM_013261.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.85
• Publications: 47 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 4-23813899-C-T is Benign according to our data. Variant chr4-23813899-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060606.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.1584G>A	p.Thr528Thr	synonymous_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.1584G>A	p.Thr528Thr	synonymous_variant	Exon 8 of 13	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52349 AN: 151850 Hom.: 9532 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.388

GnomAD2 exomes AF: 0.370 AC: 92700 AN: 250224 AF XY: 0.375

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.427

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.391 AC: 571111 AN: 1461172 Hom.: 113384 Cov.: 52 AF XY: 0.390 AC XY: 283561 AN XY: 726890

African (AFR) AF: 0.234 AC: 7829 AN: 33462

American (AMR) AF: 0.327 AC: 14639 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12475 AN: 26128

East Asian (EAS) AF: 0.447 AC: 17724 AN: 39692

South Asian (SAS) AF: 0.328 AC: 28301 AN: 86228

European-Finnish (FIN) AF: 0.340 AC: 18168 AN: 53398

Middle Eastern (MID) AF: 0.451 AC: 2600 AN: 5760

European-Non Finnish (NFE) AF: 0.401 AC: 445601 AN: 1111416

Other (OTH) AF: 0.394 AC: 23774 AN: 60374

GnomAD4 genome AF: 0.344 AC: 52345 AN: 151968 Hom.: 9525 Cov.: 32 AF XY: 0.342 AC XY: 25414 AN XY: 74278

African (AFR) AF: 0.240 AC: 9960 AN: 41454

American (AMR) AF: 0.360 AC: 5492 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1658 AN: 3468

East Asian (EAS) AF: 0.430 AC: 2215 AN: 5146

South Asian (SAS) AF: 0.330 AC: 1585 AN: 4806

European-Finnish (FIN) AF: 0.332 AC: 3514 AN: 10578

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26697 AN: 67936

Other (OTH) AF: 0.383 AC: 808 AN: 2108

Alfa AF: 0.384 Hom.: 21779

Bravo AF: 0.347

Asia WGS AF: 0.376 AC: 1310 AN: 3478

EpiCase AF: 0.409

EpiControl AF: 0.417

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPARGC1A-related disorder Benign:1

Oct 18, 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
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs3755863; hg19: chr4-23815522; COSMIC: COSV53525441; COSMIC: COSV53525441;