6-35411206-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006238.5(PPARD):c.119G>A(p.Ser40Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000101 in 1,388,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PPARD NM_006238.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18661675).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARD	NM_006238.5	c.119G>A	p.Ser40Asn	missense_variant	3/8	ENST00000360694.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARD	ENST00000360694.8	c.119G>A	p.Ser40Asn	missense_variant	3/8	2	NM_006238.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000468 AC: 9 AN: 192280 Hom.: 0 AF XY: 0.0000485 AC XY: 5 AN XY: 103174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1388056 Hom.: 0 Cov.: 33 AF XY: 0.00000872 AC XY: 6 AN XY: 688158

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: 0.0000195

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000509 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.119G>A (p.S40N) alteration is located in exon 4 (coding exon 1) of the PPARD gene. This alteration results from a G to A substitution at nucleotide position 119, causing the serine (S) at amino acid position 40 to be replaced by an asparagine (N). 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	0.14
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.66	T;T;T;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.97	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.54	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.016	D;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.58	.;P;.;P
Vest4		0.50
MutPred		0.20		Loss of glycosylation at S40 (P = 0.0045);Loss of glycosylation at S40 (P = 0.0045);Loss of glycosylation at S40 (P = 0.0045);Loss of glycosylation at S40 (P = 0.0045);
MVP		0.79
MPC		1.2
ClinPred		0.13	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772723177; hg19: chr6-35378983;