rs1800243

Positions:

• chr22-46235199-G-A
• chr22-46235199-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005036.6(PPARA):​c.1226G>A​(p.Arg409Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.699

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0920282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARA	NM_005036.6	c.1226G>A	p.Arg409Lys	missense_variant	9/9	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.1226G>A	p.Arg409Lys	missense_variant	9/9	1	NM_005036.6	ENSP00000385523.1
PPARA	ENST00000402126.1	c.1226G>A	p.Arg409Lys	missense_variant	7/7	1		ENSP00000385246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.7
DANN	Benign	0.91
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.68	T;.;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.038
MutPred		0.51		Gain of ubiquitination at R409 (P = 0.0267);Gain of ubiquitination at R409 (P = 0.0267);Gain of ubiquitination at R409 (P = 0.0267);
MVP		0.77
ClinPred		0.071	T
GERP RS		1.0
Varity_R		0.48
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800243; hg19: chr22-46631096;