22-46198038-T-C

Variant names:

• chr22-46198038-T-C
• rs4253705
• NM_005036.6:c.-42-304T>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.-42-304T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 150,476 control chromosomes in the GnomAD database, including 6,502 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 0.28 (6502 hom., cov: 29)
• Consequence: PPARA NM_005036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.442
• Publications: 2 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 (AFR) allele frequency at 95% confidence interval = 0.41 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	NM_005036.6	MANE Select	c.-42-304T>C		intron	N/A	NP_005027.2
	PPARA	NM_001001928.4		c.-42-304T>C		intron	N/A	NP_001001928.1	Q07869-1
	PPARA	NM_001001929.3		c.-42-304T>C		intron	N/A	NP_001001929.1	Q07869-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	ENST00000407236.6	TSL:1 MANE Select	c.-42-304T>C		intron	N/A	ENSP00000385523.1	Q07869-1
	PPARA	ENST00000402126.2	TSL:1	c.-39-307T>C		intron	N/A	ENSP00000385246.1	Q07869-1
	PPARA	ENST00000440343.5	TSL:1	c.-42-304T>C		intron	N/A	ENSP00000397291.1	Q86SF0

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42256 AN: 150362 Hom.: 6474 Cov.: 29

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.271

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

GnomAD4 genome AF: 0.281 AC: 42329 AN: 150476 Hom.: 6502 Cov.: 29 AF XY: 0.277 AC XY: 20363 AN XY: 73494

African (AFR) AF: 0.416 AC: 16996 AN: 40894

American (AMR) AF: 0.319 AC: 4811 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 813 AN: 3460

East Asian (EAS) AF: 0.145 AC: 741 AN: 5114

South Asian (SAS) AF: 0.157 AC: 747 AN: 4756

European-Finnish (FIN) AF: 0.173 AC: 1768 AN: 10196

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.230 AC: 15547 AN: 67680

Other (OTH) AF: 0.268 AC: 557 AN: 2082

Alfa AF: 0.109 Hom.: 154

Bravo AF: 0.299

Asia WGS AF: 0.188 AC: 653 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	4.4
DANN	Benign	0.42
PhyloP100		0.44
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: rs4253705; hg19: chr22-46593935;