rs1800206

Variant names:

Variant summary

Our verdict is The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BA1PP3BP6

The NM_005036.6(PPARA):c.484C>G (p.Leu162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0573 (AC=92,426) in the gnomAD database across 1,614,008 control chromosomes, including 3,094 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0673. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.042 ( 172 hom., cov: 30)

Exomes 𝑓: 0.059 ( 2922 hom. )

Consequence

PPARA
NM_005036.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.00

Publications

268 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 Gene-Disease associations (from GenCC):

cholesterol metabolism disease
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

PPARA links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005036.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -8 points.

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

BP6

ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.0673 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPARA	NM_005036.6	MANE Select	c.484C>G	p.Leu162Val	missense	Exon 6 of 9	NP_005027.2
PPARA	NM_001001928.4		c.484C>G	p.Leu162Val	missense	Exon 5 of 8	NP_001001928.1	Q07869-1
PPARA	NM_001001929.3		c.484C>G	p.Leu162Val	missense	Exon 4 of 7	NP_001001929.1	Q07869-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPARA	ENST00000407236.6	TSL:1 MANE Select	c.484C>G	p.Leu162Val	missense	Exon 6 of 9	ENSP00000385523.1	Q07869-1
PPARA	ENST00000402126.2	TSL:1	c.484C>G	p.Leu162Val	missense	Exon 5 of 8	ENSP00000385246.1	Q07869-1
PPARA	ENST00000493286.1	TSL:1	n.694C>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.0422

AC:

6425

AN:

152108

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.0714

Gnomad AMR

AF:

0.0504

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0228

Gnomad FIN

AF:

0.0300

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0643

Gnomad OTH

AF:

0.0606

GnomAD2 exomes

AF:

0.0434

AC:

10923

AN:

251492

AF XY:

0.0433

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.0402

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0626

Gnomad OTH exome

AF:

0.0572

GnomAD4 exome

AF:

0.0588

AC:

86009

AN:

1461782

Hom.:

2922

Cov.:

AF XY:

0.0578

AC XY:

42060

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00923

AC:

309

AN:

33478

American (AMR)

AF:

0.0429

AC:

1917

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

1084

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.0251

AC:

2169

AN:

86256

European-Finnish (FIN)

AF:

0.0339

AC:

1809

AN:

53410

Middle Eastern (MID)

AF:

0.0409

AC:

236

AN:

5766

European-Non Finnish (NFE)

AF:

0.0677

AC:

75284

AN:

1111924

Other (OTH)

AF:

0.0529

AC:

3197

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

4987

9974

14960

19947

24934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2778

5556

8334

11112

13890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0422

AC:

6417

AN:

152226

Hom.:

172

Cov.:

AF XY:

0.0399

AC XY:

2972

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0124

AC:

515

AN:

41542

American (AMR)

AF:

0.0503

AC:

769

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0395

AC:

137

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4822

European-Finnish (FIN)

AF:

0.0300

AC:

318

AN:

10598

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0642

AC:

4368

AN:

68020

Other (OTH)

AF:

0.0586

AC:

124

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

317

635

952

1270

1587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0569

Hom.:

Bravo

AF:

0.0436

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0678

EpiControl

AF:

0.0649

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.000122

AC:

AN:

122662

Turkish Variome

AF:

0.0411

AC:

276

AN:

6716

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000112

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0559

AC:

131

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperapobetalipoproteinemia, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0067

MetaSVM

Uncertain

0.056

MutationAssessor

Benign

1.7

PhyloP100

6.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.052

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.81

Mutation Taster

=72/28

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over