rs2229245

Variant names:

• chr22-46235156-G-A
• rs2229245
• NM_005036.6:c.1183G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-46235156-G-A
• chr22-46235156-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005036.6(PPARA):​c.1183G>A​(p.Gly395Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPARA NM_005036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.915
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.124592364).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	NM_005036.6	MANE Select	c.1183G>A	p.Gly395Arg	missense	Exon 9 of 9	NP_005027.2
	PPARA	NM_001001928.4		c.1183G>A	p.Gly395Arg	missense	Exon 8 of 8	NP_001001928.1
	PPARA	NM_001001929.3		c.1183G>A	p.Gly395Arg	missense	Exon 7 of 7	NP_001001929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARA	ENST00000407236.6	TSL:1 MANE Select	c.1183G>A	p.Gly395Arg	missense	Exon 9 of 9	ENSP00000385523.1
	PPARA	ENST00000402126.2	TSL:1	c.1183G>A	p.Gly395Arg	missense	Exon 8 of 8	ENSP00000385246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.92
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.10		Gain of solvent accessibility (P = 0.0306)
MVP		0.90
ClinPred		0.15	T
GERP RS		4.5
Varity_R		0.32
gMVP		0.47
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs2229245; hg19: chr22-46631053;