chr4-23852860-A-G

Variant names:

• chr4-23852860-A-G
• rs12374408
• NM_013261.5:c.235-21109T>C

Variant summary

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

The NM_013261.5(PPARGC1A):​c.235-21109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 152,028 control chromosomes in the GnomAD database, including 40,149 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 0.72 (40149 hom., cov: 32)
• Consequence: PPARGC1A NM_013261.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1A	NM_013261.5	c.235-21109T>C		intron_variant	Intron 2 of 12	ENST00000264867.7	NP_037393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.235-21109T>C		intron_variant	Intron 2 of 12	1	NM_013261.5	ENSP00000264867.2

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110039 AN: 151910 Hom.: 40102 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.846

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.715

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.724 AC: 110144 AN: 152028 Hom.: 40149 Cov.: 32 AF XY: 0.725 AC XY: 53907 AN XY: 74314

African (AFR) AF: 0.723 AC: 29949 AN: 41444

American (AMR) AF: 0.690 AC: 10523 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2407 AN: 3472

East Asian (EAS) AF: 0.611 AC: 3146 AN: 5152

South Asian (SAS) AF: 0.637 AC: 3081 AN: 4834

European-Finnish (FIN) AF: 0.805 AC: 8512 AN: 10572

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50027 AN: 67990

Other (OTH) AF: 0.719 AC: 1511 AN: 2102

Alfa AF: 0.710 Hom.: 6052

Bravo AF: 0.714

Asia WGS AF: 0.632 AC: 2197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.30
PhyloP100		-0.81
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: rs12374408; hg19: chr4-23854483;