22-46219983-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0050 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (127 hom.)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.771

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 760 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARA	NM_005036.6	c.680T>C	p.Val227Ala	missense_variant	7/9	ENST00000407236.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARA	ENST00000407236.6	c.680T>C	p.Val227Ala	missense_variant	7/9	1	NM_005036.6	P1
PPARA	ENST00000402126.1	c.680T>C	p.Val227Ala	missense_variant	5/7	1		P1
PPARA	ENST00000493286.1	n.890T>C		non_coding_transcript_exon_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 760 AN: 152080 Hom.: 17 Cov.: 32

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

GnomAD3 exomes AF: 0.0112 AC: 2820 AN: 251378 Hom.: 75 AF XY: 0.00915 AC XY: 1243 AN XY: 135870

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 SAS exome AF: 0.00268

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.: 31 AF XY: 0.00327 AC XY: 2381 AN XY: 727222

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0481

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0503

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00403

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00501 AC: 763 AN: 152198 Hom.: 18 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74414

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0432

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00257 Hom.: 16

Bravo AF: 0.00811

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00958 AC: 1163

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

PPARA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2020

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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
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	D
LIST_S2	Benign	0.82	T;.;.
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.66	D;D;D;D;D
PrimateAI	Benign	0.34	T
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	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs1800234; hg19: chr22-46615880; COSMIC: COSV53078755; COSMIC: COSV53078755;