chr4-23828615-A-G

Variant names:

• chr4-23828615-A-G
• rs2290604
• NM_013261.5:c.553-11T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_013261.5(PPARGC1A):​c.553-11T>C variant causes a intron change. The variant allele was found at a frequency of 0.0818 in 1,612,744 control chromosomes in the GnomAD database, including 6,241 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.084 (603 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5638 hom.)
• Consequence: PPARGC1A NM_013261.5 intron
• Scores: Splicing: ADA: 0.1777
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13
• Publications: 14 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 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.553-11T>C		intron	N/A	NP_037393.1
	PPARGC1A	NM_001330751.2		c.568-11T>C		intron	N/A	NP_001317680.1
	PPARGC1A	NM_001354825.2		c.568-11T>C		intron	N/A	NP_001341754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.553-11T>C		intron	N/A	ENSP00000264867.2
	PPARGC1A	ENST00000613098.4	TSL:1	c.172-11T>C		intron	N/A	ENSP00000481498.1
	PPARGC1A	ENST00000506055.5	TSL:1	n.553-11T>C		intron	N/A	ENSP00000423075.1

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12798 AN: 152058 Hom.: 604 Cov.: 32

Gnomad AFR AF: 0.0597

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.0997

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0742

Gnomad OTH AF: 0.0923

GnomAD2 exomes AF: 0.100 AC: 25218 AN: 251006 AF XY: 0.101

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.193

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0815 AC: 119102 AN: 1460568 Hom.: 5638 Cov.: 32 AF XY: 0.0833 AC XY: 60555 AN XY: 726722

African (AFR) AF: 0.0561 AC: 1873 AN: 33404

American (AMR) AF: 0.109 AC: 4880 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 2587 AN: 26112

East Asian (EAS) AF: 0.201 AC: 7980 AN: 39686

South Asian (SAS) AF: 0.130 AC: 11226 AN: 86210

European-Finnish (FIN) AF: 0.132 AC: 7028 AN: 53412

Middle Eastern (MID) AF: 0.0643 AC: 371 AN: 5766

European-Non Finnish (NFE) AF: 0.0700 AC: 77778 AN: 1110956

Other (OTH) AF: 0.0892 AC: 5379 AN: 60336

GnomAD4 genome AF: 0.0841 AC: 12794 AN: 152176 Hom.: 603 Cov.: 32 AF XY: 0.0895 AC XY: 6655 AN XY: 74386

African (AFR) AF: 0.0595 AC: 2470 AN: 41544

American (AMR) AF: 0.0998 AC: 1524 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 346 AN: 3470

East Asian (EAS) AF: 0.192 AC: 990 AN: 5146

South Asian (SAS) AF: 0.149 AC: 717 AN: 4808

European-Finnish (FIN) AF: 0.129 AC: 1368 AN: 10608

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0742 AC: 5046 AN: 68006

Other (OTH) AF: 0.0908 AC: 192 AN: 2114

Alfa AF: 0.0729 Hom.: 164

Bravo AF: 0.0792

Asia WGS AF: 0.145 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.80
PhyloP100		5.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.050		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: rs2290604; hg19: chr4-23830238; COSMIC: COSV53524555; COSMIC: COSV53524555;