22-46220008-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_005036.6(PPARA):c.705C>T(p.Asn235=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,030 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0099 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: PPARA NM_005036.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 22-46220008-C-T is Benign according to our data. Variant chr22-46220008-C-T is described in ClinVar as [Benign]. Clinvar id is 786696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00989 (1506/152322) while in subpopulation AFR AF= 0.0342 (1422/41562). AF 95% confidence interval is 0.0327. There are 24 homozygotes in gnomad4. There are 724 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARA	NM_005036.6	c.705C>T	p.Asn235=	synonymous_variant	7/9	ENST00000407236.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARA	ENST00000407236.6	c.705C>T	p.Asn235=	synonymous_variant	7/9	1	NM_005036.6	P1
PPARA	ENST00000402126.1	c.705C>T	p.Asn235=	synonymous_variant	5/7	1		P1
PPARA	ENST00000493286.1	n.915C>T		non_coding_transcript_exon_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152204 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00248 AC: 624 AN: 251118 Hom.: 8 AF XY: 0.00197 AC XY: 268 AN XY: 135778

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00110 AC: 1610 AN: 1461708 Hom.: 23 Cov.: 31 AF XY: 0.00101 AC XY: 732 AN XY: 727158

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00989 AC: 1506 AN: 152322 Hom.: 24 Cov.: 32 AF XY: 0.00972 AC XY: 724 AN XY: 74490

Gnomad4 AFR AF: 0.0342

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00307 Hom.: 14

Bravo AF: 0.0113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	8.4
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1800235; hg19: chr22-46615905; COSMIC: COSV99415568; COSMIC: COSV99415568;