6-35424654-G-C

Variant names:

• chr6-35424654-G-C
• rs756560599
• NM_006238.5:c.953G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006238.5(PPARD):​c.953G>C​(p.Arg318Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPARD NM_006238.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.95
• Publications: 0 publications found

Genes affected

PPARD (HGNC:9235): (peroxisome proliferator activated receptor delta) This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) family. The encoded protein is thought to function as an integrator of transcriptional repression and nuclear receptor signaling. It may inhibit the ligand-induced transcriptional activity of peroxisome proliferator activated receptors alpha and gamma, though evidence for this effect is inconsistent. Expression of this gene in colorectal cancer cells may be variable but is typically relatively low. Knockout studies in mice suggested a role for this protein in myelination of the corpus callosum, lipid metabolism, differentiation, and epidermal cell proliferation. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006238.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARD	NM_006238.5	MANE Select	c.953G>C	p.Arg318Pro	missense	Exon 7 of 8	NP_006229.1	Q03181-1
	PPARD	NM_001171818.2		c.953G>C	p.Arg318Pro	missense	Exon 8 of 9	NP_001165289.1	Q03181-1
	PPARD	NM_001171819.2		c.836G>C	p.Arg279Pro	missense	Exon 6 of 7	NP_001165290.1	Q03181-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARD	ENST00000360694.8	TSL:2 MANE Select	c.953G>C	p.Arg318Pro	missense	Exon 7 of 8	ENSP00000353916.3	Q03181-1
	PPARD	ENST00000311565.4	TSL:5	c.953G>C	p.Arg318Pro	missense	Exon 8 of 9	ENSP00000310928.4	Q03181-1
	PPARD	ENST00000875334.1		c.953G>C	p.Arg318Pro	missense	Exon 6 of 7	ENSP00000545393.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.62		Loss of MoRF binding (P = 0.0283)
MVP		0.97
MPC		2.2
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs756560599; hg19: chr6-35392431;