22-46198589-C-G

Variant names:

• chr22-46198589-C-G
• rs561580529
• NM_005036.6:c.206C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_005036.6(PPARA):​c.206C>G​(p.Thr69Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,459,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T69M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PPARA NM_005036.6 missense, splice_region
• Scores: Splicing: ADA: 0.0005826
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARA	NM_005036.6	c.206C>G	p.Thr69Arg	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000407236.6	NP_005027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARA	ENST00000407236.6	c.206C>G	p.Thr69Arg	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_005036.6	ENSP00000385523.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1459794 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726232

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1110668

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.206C>G (p.T69R) alteration is located in exon 4 (coding exon 1) of the PPARA gene. This alteration results from a C to G substitution at nucleotide position 206, causing the threonine (T) at amino acid position 69 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.14	.;T;.;T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;T;D;.;.
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.55	D;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.0	.;M;.;M;M
PhyloP100		2.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D;N;N;N;N
REVEL	Uncertain	0.40
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		0.52, 0.52, 0.52
MutPred		0.20		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		0.92	D
GERP RS		3.6
Varity_R		0.034
gMVP		0.60
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00058
dbscSNV1_RF	Benign	0.048
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

Other links and lift over

dbSNP: rs561580529; hg19: chr22-46594486;