6-35424147-C-T

Variant names:

• chr6-35424147-C-T
• rs759163941
• NM_006238.5:c.626C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006238.5(PPARD):​c.626C>T​(p.Ala209Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000226 in 1,459,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PPARD NM_006238.5 missense, splice_region
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARD	NM_006238.5	c.626C>T	p.Ala209Val	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000360694.8	NP_006229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARD	ENST00000360694.8	c.626C>T	p.Ala209Val	missense_variant, splice_region_variant	Exon 6 of 8	2	NM_006238.5	ENSP00000353916.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248798 AF XY: 0.0000445

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: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1459976 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 726340

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.626C>T (p.A209V) alteration is located in exon 7 (coding exon 4) of the PPARD gene. This alteration results from a C to T substitution at nucleotide position 626, causing the alanine (A) at amino acid position 209 to be replaced by a valine (V). 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	0.093
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;.;.;D
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T;T;T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;.;L;L
PhyloP100		5.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.052	T;D;D;D;D
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.69	.;P;.;.;P
Vest4		0.11
MutPred		0.38		.;Gain of ubiquitination at K204 (P = 0.0828);.;Gain of ubiquitination at K204 (P = 0.0828);Gain of ubiquitination at K204 (P = 0.0828);
MVP		0.42
MPC		0.76
ClinPred		0.15	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.28
gMVP		0.33
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.040		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: rs759163941; hg19: chr6-35391924;