rs4253725

Variant names:

• chr22-46213021-T-A
• rs4253725
• NM_005036.6:c.209-2152T>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.209-2152T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,048 control chromosomes in the GnomAD database, including 8,931 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 0.32 (8931 hom., cov: 32)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.537
• Publications: 1 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.209-2152T>A		intron_variant	Intron 4 of 8	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.209-2152T>A		intron_variant	Intron 4 of 8	1	NM_005036.6	ENSP00000385523.1
PPARA	ENST00000402126.2	c.209-2152T>A		intron_variant	Intron 3 of 7	1		ENSP00000385246.1
PPARA	ENST00000493286.1	n.419-2152T>A		intron_variant	Intron 3 of 5	1
PPARA	ENST00000420804.5	c.209-2152T>A		intron_variant	Intron 3 of 3	2		ENSP00000414752.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47997 AN: 151930 Hom.: 8908 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.316 AC: 48055 AN: 152048 Hom.: 8931 Cov.: 32 AF XY: 0.307 AC XY: 22819 AN XY: 74328

African (AFR) AF: 0.515 AC: 21345 AN: 41450

American (AMR) AF: 0.239 AC: 3654 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5174

South Asian (SAS) AF: 0.126 AC: 609 AN: 4824

European-Finnish (FIN) AF: 0.195 AC: 2065 AN: 10576

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.269 AC: 18287 AN: 67970

Other (OTH) AF: 0.315 AC: 667 AN: 2116

Alfa AF: 0.289 Hom.: 1024

Bravo AF: 0.330

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.71
DANN	Benign	0.67
PhyloP100		-0.54
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: rs4253725; hg19: chr22-46608918;