rs4253754

Variant names:

• chr22-46219247-G-A
• rs4253754
• NM_005036.6:c.509-565G>A

Variant summary

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

The NM_005036.6(PPARA):​c.509-565G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 152,170 control chromosomes in the GnomAD database, including 2,270 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 0.17 (2270 hom., cov: 32)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.509-565G>A		intron_variant	Intron 6 of 8	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.509-565G>A		intron_variant	Intron 6 of 8	1	NM_005036.6	ENSP00000385523.1
PPARA	ENST00000402126.2	c.509-565G>A		intron_variant	Intron 5 of 7	1		ENSP00000385246.1
PPARA	ENST00000493286.1	n.719-565G>A		intron_variant	Intron 5 of 5	1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25510 AN: 152052 Hom.: 2275 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.168 AC: 25509 AN: 152170 Hom.: 2270 Cov.: 32 AF XY: 0.163 AC XY: 12148 AN XY: 74378

African (AFR) AF: 0.141 AC: 5839 AN: 41524

American (AMR) AF: 0.151 AC: 2310 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.106 AC: 511 AN: 4816

European-Finnish (FIN) AF: 0.138 AC: 1461 AN: 10586

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14025 AN: 67988

Other (OTH) AF: 0.186 AC: 393 AN: 2112

Alfa AF: 0.191 Hom.: 5582

Bravo AF: 0.169

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.73
PhyloP100		-0.12
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: rs4253754; hg19: chr22-46615144;