22-46160138-T-C

Variant names:

• chr22-46160138-T-C
• rs135542
• NM_005036.6:c.-127+8168T>C

Variant summary

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

The NM_005036.6(PPARA):​c.-127+8168T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,108 control chromosomes in the GnomAD database, including 5,129 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 0.25 (5129 hom., cov: 33)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926
• Publications: 13 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.-127+8168T>C		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.-127+8168T>C		intron_variant	Intron 2 of 8	1	NM_005036.6	ENSP00000385523.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38411 AN: 151990 Hom.: 5125 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.253 AC: 38448 AN: 152108 Hom.: 5129 Cov.: 33 AF XY: 0.247 AC XY: 18366 AN XY: 74364

African (AFR) AF: 0.274 AC: 11382 AN: 41476

American (AMR) AF: 0.188 AC: 2870 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3472

East Asian (EAS) AF: 0.0791 AC: 410 AN: 5182

South Asian (SAS) AF: 0.154 AC: 745 AN: 4826

European-Finnish (FIN) AF: 0.247 AC: 2607 AN: 10570

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18831 AN: 67984

Other (OTH) AF: 0.259 AC: 548 AN: 2116

Alfa AF: 0.263 Hom.: 6790

Bravo AF: 0.251

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
PhyloP100		-0.93

Splicing

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

Other links and lift over

dbSNP: rs135542; hg19: chr22-46556037;