6-35411021-G-A

Variant names:

• chr6-35411021-G-A
• rs9658134
• NM_006238.5:c.-67G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006238.5(PPARD):​c.-67G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,383,208 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.013 (125 hom.)
• Consequence: PPARD NM_006238.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1958/152234) while in subpopulation AFR AF = 0.0188 (780/41518). AF 95% confidence interval is 0.0177. There are 18 homozygotes in GnomAd4. There are 844 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1958 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARD	NM_006238.5	MANE Select	c.-67G>A		5_prime_UTR	Exon 3 of 8	NP_006229.1
	PPARD	NM_001171818.2		c.-67G>A		5_prime_UTR	Exon 4 of 9	NP_001165289.1
	PPARD	NM_177435.3		c.-67G>A		5_prime_UTR	Exon 3 of 7	NP_803184.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARD	ENST00000360694.8	TSL:2 MANE Select	c.-67G>A		5_prime_UTR	Exon 3 of 8	ENSP00000353916.3
	PPARD	ENST00000311565.4	TSL:5	c.-67G>A		5_prime_UTR	Exon 4 of 9	ENSP00000310928.4
	PPARD	ENST00000337400.6	TSL:5	c.-67G>A		5_prime_UTR	Exon 4 of 8	ENSP00000337063.2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1956 AN: 152116 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0134 AC: 16466 AN: 1230974 Hom.: 125 Cov.: 33 AF XY: 0.0130 AC XY: 7806 AN XY: 598482

African (AFR) AF: 0.0199 AC: 516 AN: 25932

American (AMR) AF: 0.00419 AC: 73 AN: 17420

Ashkenazi Jewish (ASJ) AF: 0.000244 AC: 4 AN: 16418

East Asian (EAS) AF: 0.00 AC: 0 AN: 31330

South Asian (SAS) AF: 0.0000205 AC: 1 AN: 48818

European-Finnish (FIN) AF: 0.00251 AC: 114 AN: 45352

Middle Eastern (MID) AF: 0.000411 AC: 2 AN: 4862

European-Non Finnish (NFE) AF: 0.0154 AC: 15263 AN: 991166

Other (OTH) AF: 0.00992 AC: 493 AN: 49676

GnomAD4 genome AF: 0.0129 AC: 1958 AN: 152234 Hom.: 18 Cov.: 32 AF XY: 0.0113 AC XY: 844 AN XY: 74424

African (AFR) AF: 0.0188 AC: 780 AN: 41518

American (AMR) AF: 0.00425 AC: 65 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1072 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0130 Hom.: 42

Bravo AF: 0.0133

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		-0.037
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs9658134; hg19: chr6-35378798;