chr22-46198039-G-A

Variant names:

• chr22-46198039-G-A
• rs4253706
• NM_005036.6:c.-42-303G>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.-42-303G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 150,788 control chromosomes in the GnomAD database, including 441 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 0.073 (441 hom., cov: 29)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523
• Publications: 0 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	NM_005036.6	MANE Select	c.-42-303G>A		intron	N/A	NP_005027.2
	PPARA	NM_001001928.4		c.-42-303G>A		intron	N/A	NP_001001928.1
	PPARA	NM_001001929.3		c.-42-303G>A		intron	N/A	NP_001001929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	ENST00000407236.6	TSL:1 MANE Select	c.-42-303G>A		intron	N/A	ENSP00000385523.1
	PPARA	ENST00000402126.2	TSL:1	c.-39-306G>A		intron	N/A	ENSP00000385246.1
	PPARA	ENST00000440343.5	TSL:1	c.-42-303G>A		intron	N/A	ENSP00000397291.1

Frequencies

GnomAD3 genomes AF: 0.0732 AC: 11031 AN: 150670 Hom.: 442 Cov.: 29

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0741

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

GnomAD4 genome AF: 0.0731 AC: 11030 AN: 150788 Hom.: 441 Cov.: 29 AF XY: 0.0702 AC XY: 5169 AN XY: 73676

African (AFR) AF: 0.0382 AC: 1567 AN: 41022

American (AMR) AF: 0.0657 AC: 993 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3468

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5120

South Asian (SAS) AF: 0.0527 AC: 252 AN: 4784

European-Finnish (FIN) AF: 0.0633 AC: 647 AN: 10226

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6878 AN: 67762

Other (OTH) AF: 0.0733 AC: 153 AN: 2086

Alfa AF: 0.0834 Hom.: 87

Bravo AF: 0.0724

Asia WGS AF: 0.0320 AC: 112 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.8
DANN	Benign	0.76
PhyloP100		0.52
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: rs4253706; hg19: chr22-46593936;