chr4-23889159-G-A

Variant names:

• chr4-23889159-G-A
• rs3774902
• NM_013261.5:c.54+745C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013261.5(PPARGC1A):​c.54+745C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 985,174 control chromosomes in the GnomAD database, including 2,512 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 0.090 (998 hom., cov: 32)
  • Exomes 𝑓: 0.051 (1514 hom.)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.462
• Publications: 10 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=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 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.54+745C>T		intron	N/A	NP_037393.1
	PPARGC1A	NM_001330751.2		c.70-4228C>T		intron	N/A	NP_001317680.1
	PPARGC1A	NM_001354825.2		c.70-4228C>T		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.54+745C>T		intron	N/A	ENSP00000264867.2
	PPARGC1A	ENST00000506055.5	TSL:1	n.54+745C>T		intron	N/A	ENSP00000423075.1
	PPARGC1A	ENST00000513205.5	TSL:1	n.54+745C>T		intron	N/A	ENSP00000421632.1

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13689 AN: 152010 Hom.: 995 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0512

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0512 AC: 42623 AN: 833046 Hom.: 1514 Cov.: 31 AF XY: 0.0510 AC XY: 19621 AN XY: 384688

African (AFR) AF: 0.0791 AC: 1249 AN: 15782

American (AMR) AF: 0.162 AC: 159 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 511 AN: 5152

East Asian (EAS) AF: 0.355 AC: 1288 AN: 3628

South Asian (SAS) AF: 0.161 AC: 2650 AN: 16458

European-Finnish (FIN) AF: 0.0797 AC: 22 AN: 276

Middle Eastern (MID) AF: 0.130 AC: 211 AN: 1620

European-Non Finnish (NFE) AF: 0.0450 AC: 34268 AN: 761848

Other (OTH) AF: 0.0830 AC: 2265 AN: 27298

GnomAD4 genome AF: 0.0900 AC: 13695 AN: 152128 Hom.: 998 Cov.: 32 AF XY: 0.0968 AC XY: 7201 AN XY: 74368

African (AFR) AF: 0.0778 AC: 3232 AN: 41518

American (AMR) AF: 0.168 AC: 2571 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 382 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1882 AN: 5160

South Asian (SAS) AF: 0.193 AC: 927 AN: 4804

European-Finnish (FIN) AF: 0.0902 AC: 955 AN: 10582

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0512 AC: 3480 AN: 68002

Other (OTH) AF: 0.107 AC: 225 AN: 2112

Alfa AF: 0.0715 Hom.: 737

Bravo AF: 0.0977

Asia WGS AF: 0.267 AC: 924 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		0.46
Mutation Taster		=100/0	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: rs3774902; hg19: chr4-23890782;