22-46168728-C-G

Variant names:

• chr22-46168728-C-G
• rs135538
• NM_005036.6:c.-126-8025C>G

Variant summary

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

The NM_005036.6(PPARA):​c.-126-8025C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,674 control chromosomes in the GnomAD database, including 23,455 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 0.53 (23455 hom., cov: 31)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 16 publications found

Genes affected

PPARA (HGNC:9232): (peroxisome proliferator activated receptor alpha) Peroxisome proliferators include hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers; this term arises because they induce an increase in the size and number of peroxisomes. Peroxisomes are subcellular organelles found in plants and animals that contain enzymes for respiration and for cholesterol and lipid metabolism. The action of peroxisome proliferators is thought to be mediated via specific receptors, called PPARs, which belong to the steroid hormone receptor superfamily. PPARs affect the expression of target genes involved in cell proliferation, cell differentiation and in immune and inflammation responses. Three closely related subtypes (alpha, beta/delta, and gamma) have been identified. This gene encodes the subtype PPAR-alpha, which is a nuclear transcription factor. Multiple alternatively spliced transcript variants have been described for this gene, although the full-length nature of only two has been determined. [provided by RefSeq, Jul 2008]

ENSG00000310070 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.-126-8025C>G		intron_variant	Intron 2 of 8	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.-126-8025C>G		intron_variant	Intron 2 of 8	1	NM_005036.6	ENSP00000385523.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79551 AN: 151556 Hom.: 23405 Cov.: 31

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.475

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

GnomAD4 genome AF: 0.525 AC: 79656 AN: 151674 Hom.: 23455 Cov.: 31 AF XY: 0.521 AC XY: 38605 AN XY: 74108

African (AFR) AF: 0.797 AC: 33048 AN: 41442

American (AMR) AF: 0.448 AC: 6796 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1061 AN: 3442

East Asian (EAS) AF: 0.431 AC: 2230 AN: 5174

South Asian (SAS) AF: 0.397 AC: 1908 AN: 4810

European-Finnish (FIN) AF: 0.441 AC: 4636 AN: 10510

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.419 AC: 28433 AN: 67840

Other (OTH) AF: 0.470 AC: 986 AN: 2100

Alfa AF: 0.320 Hom.: 789

Bravo AF: 0.539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.16
PhyloP100		-2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs135538; hg19: chr22-46564628;