rs17574213

Variant names:

• chr4-23814058-G-A
• rs17574213
• NM_013261.5:c.1425C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_013261.5(PPARGC1A):​c.1425C>T​(p.Asp475Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,884 control chromosomes in the GnomAD database, including 3,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.051 (229 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3677 hom.)
• Consequence: PPARGC1A NM_013261.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.565
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 4-23814058-G-A is Benign according to our data. Variant chr4-23814058-G-A is described in ClinVar as Benign. ClinVar VariationId is 3037609.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.565 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013261.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	NM_013261.5	MANE Select	c.1425C>T	p.Asp475Asp	synonymous	Exon 8 of 13	NP_037393.1
	PPARGC1A	NM_001330751.2		c.1440C>T	p.Asp480Asp	synonymous	Exon 10 of 15	NP_001317680.1
	PPARGC1A	NM_001354825.2		c.1440C>T	p.Asp480Asp	synonymous	Exon 9 of 14	NP_001341754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.1425C>T	p.Asp475Asp	synonymous	Exon 8 of 13	ENSP00000264867.2
	PPARGC1A	ENST00000613098.4	TSL:1	c.1044C>T	p.Asp348Asp	synonymous	Exon 7 of 12	ENSP00000481498.1
	PPARGC1A	ENST00000506055.5	TSL:1	n.*640C>T		non_coding_transcript_exon	Exon 8 of 13	ENSP00000423075.1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7773 AN: 152010 Hom.: 229 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0493 AC: 12361 AN: 250682 AF XY: 0.0495

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0689

Gnomad NFE exome AF: 0.0659

Gnomad OTH exome AF: 0.0506

GnomAD4 exome AF: 0.0657 AC: 96056 AN: 1461756 Hom.: 3677 Cov.: 70 AF XY: 0.0641 AC XY: 46627 AN XY: 727166

African (AFR) AF: 0.0293 AC: 979 AN: 33468

American (AMR) AF: 0.0388 AC: 1733 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 731 AN: 26132

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39688

South Asian (SAS) AF: 0.0353 AC: 3044 AN: 86246

European-Finnish (FIN) AF: 0.0695 AC: 3715 AN: 53416

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5766

European-Non Finnish (NFE) AF: 0.0740 AC: 82327 AN: 1111932

Other (OTH) AF: 0.0563 AC: 3398 AN: 60390

GnomAD4 genome AF: 0.0511 AC: 7775 AN: 152128 Hom.: 229 Cov.: 32 AF XY: 0.0497 AC XY: 3696 AN XY: 74354

African (AFR) AF: 0.0288 AC: 1197 AN: 41506

American (AMR) AF: 0.0436 AC: 667 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5148

South Asian (SAS) AF: 0.0337 AC: 162 AN: 4808

European-Finnish (FIN) AF: 0.0699 AC: 740 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0693 AC: 4714 AN: 68004

Other (OTH) AF: 0.0337 AC: 71 AN: 2108

Alfa AF: 0.0551 Hom.: 283

Bravo AF: 0.0494

Asia WGS AF: 0.0140 AC: 47 AN: 3476

EpiCase AF: 0.0613

EpiControl AF: 0.0613

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PPARGC1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		0.56
Mutation Taster		=99/1	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: rs17574213; hg19: chr4-23815681; COSMIC: COSV53524624; COSMIC: COSV53524624;