chr4-23814055-G-A

Position:

• chr4-23814055-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_013261.5(PPARGC1A):​c.1428C>T​(p.Asp476=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,946 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (7 hom.)
• Consequence: PPARGC1A NM_013261.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.405

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 4-23814055-G-A is Benign according to our data. Variant chr4-23814055-G-A is described in ClinVar as [Benign]. Clinvar id is 718433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.405 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00532 (809/152178) while in subpopulation AFR AF= 0.0178 (738/41512). AF 95% confidence interval is 0.0167. There are 8 homozygotes in gnomad4. There are 385 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 809 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.1428C>T	p.Asp476=	synonymous_variant	8/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1428C>T	p.Asp476=	synonymous_variant	8/13	1	NM_013261.5	P1
PPARGC1A	ENST00000613098.4	c.1047C>T	p.Asp349=	synonymous_variant	7/12	1
PPARGC1A	ENST00000506055.5	c.*643C>T		3_prime_UTR_variant, NMD_transcript_variant	8/13	1
PPARGC1A	ENST00000509702.5	n.1468C>T		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 807 AN: 152060 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00169 AC: 423 AN: 250744 Hom.: 4 AF XY: 0.00142 AC XY: 192 AN XY: 135474

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.000677 AC: 990 AN: 1461768 Hom.: 7 Cov.: 65 AF XY: 0.000630 AC XY: 458 AN XY: 727176

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00532 AC: 809 AN: 152178 Hom.: 8 Cov.: 32 AF XY: 0.00518 AC XY: 385 AN XY: 74382

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00280 Hom.: 1

Bravo AF: 0.00597

EpiCase AF: 0.000654

EpiControl AF: 0.000771

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

Mar 14, 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

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.68

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: rs61743310; hg19: chr4-23815678;