22-46219983-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005036.6(PPARA):c.680T>C(p.Val227Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,614,026 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 127 hom. )

Consequence

PPARA
NM_005036.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.771

Publications

69 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027141273).

BP6

Variant 22-46219983-T-C is Benign according to our data. Variant chr22-46219983-T-C is described in ClinVar as Benign. ClinVar VariationId is 770476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00501 (763/152198) while in subpopulation EAS AF = 0.0432 (224/5186). AF 95% confidence interval is 0.0386. There are 18 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 763 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6 link	c.680T>C	p.Val227Ala	missense_variant	Exon 7 of 9	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PPARA	ENST00000407236.6 link	c.680T>C	p.Val227Ala	missense_variant	Exon 7 of 9	1	NM_005036.6	ENSP00000385523.1
PPARA	ENST00000402126.2 link	c.680T>C	p.Val227Ala	missense_variant	Exon 6 of 8	1		ENSP00000385246.1
PPARA	ENST00000493286.1 link	n.890T>C		non_coding_transcript_exon_variant	Exon 6 of 6	1

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

760

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0275

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0431

Gnomad SAS

AF:

0.00312

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.0112

AC:

2820

AN:

251378

AF XY:

0.00915

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0486

Gnomad ASJ exome

AF:

0.00466

Gnomad EAS exome

AF:

0.0441

Gnomad FIN exome

AF:

0.00366

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00349

AC:

5104

AN:

1461828

Hom.:

127

Cov.:

AF XY:

0.00327

AC XY:

2381

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.0481

AC:

2152

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00325

AC:

AN:

26136

East Asian (EAS)

AF:

0.0503

AC:

1995

AN:

39696

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86258

European-Finnish (FIN)

AF:

0.00403

AC:

215

AN:

53366

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1112010

Other (OTH)

AF:

0.00416

AC:

251

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

311

622

933

1244

1555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00501

AC:

763

AN:

152198

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

443

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41540

American (AMR)

AF:

0.0277

AC:

423

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.0432

AC:

224

AN:

5186

South Asian (SAS)

AF:

0.00312

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68000

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00332

Hom.:

Bravo

AF:

0.00811

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00958

AC:

1163

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PPARA-related disorder

Benign:1

Jan 27, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.82

T;.;.

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

0.77

PrimateAI

Benign

0.34

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.080

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.056

ClinPred

0.0047

GERP RS

4.2

Varity_R

0.12

gMVP

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over