rs1188000241

Variant names:

• chr22-46219904-G-A
• rs1188000241
• NM_005036.6:c.601G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005036.6(PPARA):​c.601G>A​(p.Ala201Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.40

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38689685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.601G>A	p.Ala201Thr	missense_variant	Exon 7 of 9	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.601G>A	p.Ala201Thr	missense_variant	Exon 7 of 9	1	NM_005036.6	ENSP00000385523.1
PPARA	ENST00000402126.1	c.601G>A	p.Ala201Thr	missense_variant	Exon 5 of 7	1		ENSP00000385246.1
PPARA	ENST00000493286.1	n.811G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.601G>A (p.A201T) alteration is located in exon 7 (coding exon 4) of the PPARA gene. This alteration results from a G to A substitution at nucleotide position 601, causing the alanine (A) at amino acid position 201 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.025	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.30
MutPred		0.44		Gain of phosphorylation at A201 (P = 0.0652);Gain of phosphorylation at A201 (P = 0.0652);Gain of phosphorylation at A201 (P = 0.0652);
MVP		0.93
ClinPred		0.74	D
GERP RS		5.2
Varity_R		0.38
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs1188000241; hg19: chr22-46615801;