22-46231883-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (31 hom.)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.14

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 Benign. Variant got -10 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 criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 561 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARA	NM_005036.6	c.803C>T	p.Ala268Val	missense_variant	8/9	ENST00000407236.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARA	ENST00000407236.6	c.803C>T	p.Ala268Val	missense_variant	8/9	1	NM_005036.6	P1
PPARA	ENST00000402126.1	c.803C>T	p.Ala268Val	missense_variant	6/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 561 AN: 152202 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.00381 AC: 957 AN: 251338 Hom.: 6 AF XY: 0.00365 AC XY: 496 AN XY: 135868

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 SAS exome AF: 0.000686

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.: 31 Cov.: 32 AF XY: 0.00523 AC XY: 3806 AN XY: 727194

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00660

Gnomad4 NFE exome AF: 0.00638

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.00368 AC: 561 AN: 152320 Hom.: 1 Cov.: 31 AF XY: 0.00358 AC XY: 267 AN XY: 74486

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.00594

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00528 Hom.: 4

Bravo AF: 0.00335

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00640

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPARA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
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	D
LIST_S2	Uncertain	0.88	D;.;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.18	N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.44	T
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	T
GERP RS		4.5
Varity_R		0.41
gMVP		0.65

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: rs1042311; hg19: chr22-46627780;