Genetic Variant NM_006238.5:c.1099G>T (chr6-35425852-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006238.5(PPARD):c.1099G>T(p.Val367Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 6.8e-7 ( 0 hom. )

Consequence

PPARD
NM_006238.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.97

Variant links:

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]

PPARD links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARD	NM_006238.5 link	c.1099G>T	p.Val367Phe	missense_variant	Exon 8 of 8	ENST00000360694.8	NP_006229.1	Q03181-1A0A024RCW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPARD	ENST00000360694.8 link	c.1099G>T	p.Val367Phe	missense_variant	Exon 8 of 8	2	NM_006238.5	ENSP00000353916.3	Q03181-1
PPARD	ENST00000311565.4 link	c.1099G>T	p.Val367Phe	missense_variant	Exon 9 of 9	5		ENSP00000310928.4	Q03181-1
PPARD	ENST00000448077.6 link	c.982G>T	p.Val328Phe	missense_variant	Exon 7 of 7	2		ENSP00000414372.2	Q03181-3
PPARD	ENST00000418635.6 link	c.805G>T	p.Val269Phe	missense_variant	Exon 6 of 6	2		ENSP00000413314.2	Q03181-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D;.;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;.

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

.;M;.;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.68

MutPred

0.43

.;Loss of stability (P = 0.1629);.;Loss of stability (P = 0.1629);

MVP

0.87

MPC

2.1

ClinPred

0.99

GERP RS

5.0

Varity_R

0.71

gMVP

0.75

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over