Genetic Variant NM_006238.5:c.-67G>A (chr6-35411021-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0370

Publications

7 publications found

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 was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARD	NM_006238.5 link	c.-67G>A		5_prime_UTR_variant	Exon 3 of 8	ENST00000360694.8	NP_006229.1	Q03181-1A0A024RCW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARD	ENST00000360694.8 link	c.-67G>A		5_prime_UTR_variant	Exon 3 of 8	2	NM_006238.5	ENSP00000353916.3		Q03181-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1956

AN:

152116

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0130

AC XY:

7806

AN XY:

598482

show subpopulations

African (AFR)

AF:

0.0199

AC:

516

AN:

25932

American (AMR)

AF:

0.00419

AC:

AN:

17420

Ashkenazi Jewish (ASJ)

AF:

0.000244

AC:

AN:

16418

East Asian (EAS)

AF:

0.00

AC:

AN:

31330

South Asian (SAS)

AF:

0.0000205

AC:

AN:

48818

European-Finnish (FIN)

AF:

0.00251

AC:

114

AN:

45352

Middle Eastern (MID)

AF:

0.000411

AC:

AN:

4862

European-Non Finnish (NFE)

AF:

0.0154

AC:

15263

AN:

991166

Other (OTH)

AF:

0.00992

AC:

493

AN:

49676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

969

1938

2906

3875

4844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0129

AC:

1958

AN:

152234

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

844

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0188

AC:

780

AN:

41518

American (AMR)

AF:

0.00425

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0158

AC:

1072

AN:

68024

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

207

310

414

517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0130

Hom.:

Bravo

AF:

0.0133

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

-0.037

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

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NM_006238.5:c.-67G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over