Genetic Variant NM_005036.6:c.422G>T (chr22-46218315-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005036.6(PPARA):c.422G>T(p.Arg141Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R141H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PPARA
NM_005036.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.76

Publications

3 publications found

Variant links:

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]

PPARA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6 link	c.422G>T	p.Arg141Leu	missense_variant	Exon 6 of 9	ENST00000407236.6	NP_005027.2	Q07869-1F1D8S4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPARA	ENST00000407236.6 link	c.422G>T	p.Arg141Leu	missense_variant	Exon 6 of 9	1	NM_005036.6	ENSP00000385523.1	Q07869-1
PPARA	ENST00000402126.2 link	c.422G>T	p.Arg141Leu	missense_variant	Exon 5 of 8	1		ENSP00000385246.1	Q07869-1
PPARA	ENST00000493286.1 link	n.632G>T		non_coding_transcript_exon_variant	Exon 5 of 6	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251494

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;D;D

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;.;.

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.8

L;L;L

PhyloP100

4.8

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.57

P;P;P

Vest4

0.45

MutPred

0.62

Loss of disorder (P = 0.0393);Loss of disorder (P = 0.0393);Loss of disorder (P = 0.0393);

MVP

0.93

ClinPred

0.48

GERP RS

5.7

Varity_R

0.27

gMVP

0.88

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over