rs1042311

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005036.6(PPARA):c.803C>T(p.Ala268Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,614,122 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0054 ( 31 hom. )

Consequence

PPARA
NM_005036.6 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.14

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076411366).

BP6

Variant 22-46231883-C-T is Benign according to our data. Variant chr22-46231883-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041835.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 561 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6 link	c.803C>T	p.Ala268Val	missense_variant	Exon 8 of 9	ENST00000407236.6	NP_005027.2	Q07869-1F1D8S4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6 link	c.803C>T	p.Ala268Val	missense_variant	Exon 8 of 9	1	NM_005036.6	ENSP00000385523.1		Q07869-1
PPARA	ENST00000402126.1 link	c.803C>T	p.Ala268Val	missense_variant	Exon 6 of 7	1		ENSP00000385246.1		Q07869-1

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

561

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00594

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00381

AC:

957

AN:

251338

AF XY:

0.00365

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00615

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00543

AC:

7939

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

3806

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.00192

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.000115

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.000730

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00660

AC:

352

AN:

53372

Gnomad4 NFE exome

AF:

0.00638

AC:

7099

AN:

1111982

Gnomad4 Remaining exome

AF:

0.00479

AC:

289

AN:

60394

Heterozygous variant carriers

483

966

1448

1931

2414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.00368

AC:

561

AN:

152320

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

267

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00108

AC:

0.00108225

AN:

0.00108225

Gnomad4 AMR

AF:

0.00268

AC:

0.00268219

AN:

0.00268219

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000192976

AN:

0.000192976

Gnomad4 SAS

AF:

0.000207

AC:

0.000207039

AN:

0.000207039

Gnomad4 FIN

AF:

0.00556

AC:

0.0055587

AN:

0.0055587

Gnomad4 NFE

AF:

0.00594

AC:

0.00593803

AN:

0.00593803

Gnomad4 OTH

AF:

0.00473

AC:

0.00473037

AN:

0.00473037

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<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:

0.00511

Hom.:

Bravo

AF:

0.00335

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00594

EpiControl

AF:

0.00640

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PPARA-related disorder

Benign:1

Aug 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;.;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.0076

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.18

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.43

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.90

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.39

B;B;B

Vest4

0.19

MVP

0.94

ClinPred

0.015

GERP RS

4.5

Varity_R

0.41

gMVP

0.65

Mutation Taster

=98/2

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over