rs4253681

Variant names:

• chr22-46183703-T-C
• rs4253681
• NM_005036.6:c.-43+6867T>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.-43+6867T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,152 control chromosomes in the GnomAD database, including 3,168 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 0.20 (3168 hom., cov: 32)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 10 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.-43+6867T>C		intron_variant	Intron 3 of 8	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.-43+6867T>C		intron_variant	Intron 3 of 8	1	NM_005036.6	ENSP00000385523.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29753 AN: 152034 Hom.: 3143 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.218

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

GnomAD4 genome AF: 0.196 AC: 29823 AN: 152152 Hom.: 3168 Cov.: 32 AF XY: 0.195 AC XY: 14500 AN XY: 74388

African (AFR) AF: 0.272 AC: 11284 AN: 41494

American (AMR) AF: 0.234 AC: 3581 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 982 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1039 AN: 5178

South Asian (SAS) AF: 0.141 AC: 677 AN: 4818

European-Finnish (FIN) AF: 0.129 AC: 1370 AN: 10588

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10129 AN: 68008

Other (OTH) AF: 0.215 AC: 454 AN: 2114

Alfa AF: 0.162 Hom.: 301

Bravo AF: 0.210

Asia WGS AF: 0.177 AC: 617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.53
PhyloP100		-1.5
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: rs4253681; hg19: chr22-46579600;