22-46215209-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.245C>T(p.Thr82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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=0.0062275827).
• BP6: Variant 22-46215209-C-T is Benign according to our data. Variant chr22-46215209-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 731182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARA	NM_005036.6	c.245C>T	p.Thr82Ile	missense_variant	5/9	ENST00000407236.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARA	ENST00000407236.6	c.245C>T	p.Thr82Ile	missense_variant	5/9	1	NM_005036.6	P1
PPARA	ENST00000402126.1	c.245C>T	p.Thr82Ile	missense_variant	3/7	1		P1
PPARA	ENST00000493286.1	n.455C>T		non_coding_transcript_exon_variant	4/6	1
PPARA	ENST00000420804.5	c.245C>T	p.Thr82Ile	missense_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251424 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135882

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000144 AC: 211 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727234

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74472

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.00117

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.73	T;T;.;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Benign	0.90	L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.0	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0090	B;.;B;B
Vest4		0.043
MVP		0.90
ClinPred		0.011	T
GERP RS		-0.71
Varity_R		0.041
gMVP		0.20

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: rs142150973; hg19: chr22-46611106;