NM_005036.6:c.206C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005036.6(PPARA):c.206C>T(p.Thr69Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000683 in 1,611,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T69R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

PPARA
NM_005036.6 missense, splice_region

Scores

Splicing: ADA: 0.004128

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06969732).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6 link	c.206C>T	p.Thr69Met	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000407236.6	NP_005027.2	Q07869-1F1D8S4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6 link	c.206C>T	p.Thr69Met	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_005036.6	ENSP00000385523.1		Q07869-1

Frequencies

GnomAD3 genomes

AF:

0.0000528

AC:

AN:

151644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

250714

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000699

AC:

102

AN:

1459792

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.0000448

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00106

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110666

Other (OTH)

AF:

0.0000664

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151730

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41360

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00167

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.206C>T (p.T69M) alteration is located in exon 4 (coding exon 1) of the PPARA gene. This alteration results from a C to T substitution at nucleotide position 206, causing the threonine (T) at amino acid position 69 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;.;T;T

Eigen

Benign

-0.076

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

D;D;D;.;.

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.070

T;T;T;T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.0

.;M;.;M;M

PhyloP100

2.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;T;T;T;T

Sift4G

Pathogenic

0.0

D;T;T;T;T

Polyphen

0.98

.;D;.;D;D

Vest4

0.58, 0.56

MutPred

0.22

Loss of glycosylation at T69 (P = 0.0127);Loss of glycosylation at T69 (P = 0.0127);Loss of glycosylation at T69 (P = 0.0127);Loss of glycosylation at T69 (P = 0.0127);Loss of glycosylation at T69 (P = 0.0127);

MVP

0.95

ClinPred

0.17

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.013

gMVP

0.37

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0041

dbscSNV1_RF

Benign

0.068

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

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NM_005036.6:c.206C>T

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