Genetic Variant PDK4:c.1095+75T>C (chr7-95586935-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002612.4(PDK4):c.1095+75T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 801,930 control chromosomes in the GnomAD database, including 67,396 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 0.43 ( 15031 hom., cov: 32)

Exomes 𝑓: 0.39 ( 52365 hom. )

Consequence

PDK4
NM_002612.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0910

Publications

9 publications found

Variant links:

Genes affected

PDK4 (HGNC:8812): (pyruvate dehydrogenase kinase 4) This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]

PDK4 links:

PDK4-AS1 (HGNC:55767): (PDK4 antisense RNA 1)

PDK4-AS1 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=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK4	NM_002612.4 link	c.1095+75T>C		intron_variant	Intron 10 of 10	ENST00000005178.6	NP_002603.1	Q16654A4D1H4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK4	ENST00000005178.6 link	c.1095+75T>C		intron_variant	Intron 10 of 10	1	NM_002612.4	ENSP00000005178.5		Q16654

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

65624

AN:

151932

Hom.:

15008

Cov.:

show subpopulations

Gnomad AFR

AF:

0.542

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.472

Gnomad EAS

AF:

0.830

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.462

GnomAD4 exome

AF:

0.385

AC:

250235

AN:

649880

Hom.:

52365

Cov.:

AF XY:

0.387

AC XY:

133723

AN XY:

345724

show subpopulations

African (AFR)

AF:

0.529

AC:

9064

AN:

17126

American (AMR)

AF:

0.376

AC:

12673

AN:

33734

Ashkenazi Jewish (ASJ)

AF:

0.460

AC:

8130

AN:

17688

East Asian (EAS)

AF:

0.772

AC:

27269

AN:

35306

South Asian (SAS)

AF:

0.435

AC:

25847

AN:

59368

European-Finnish (FIN)

AF:

0.304

AC:

15084

AN:

49660

Middle Eastern (MID)

AF:

0.492

AC:

1851

AN:

3762

European-Non Finnish (NFE)

AF:

0.341

AC:

136639

AN:

400288

Other (OTH)

AF:

0.415

AC:

13678

AN:

32948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

6433

12865

19298

25730

32163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1948

3896

5844

7792

9740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.432

AC:

65691

AN:

152050

Hom.:

15031

Cov.:

AF XY:

0.432

AC XY:

32097

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.543

AC:

22515

AN:

41470

American (AMR)

AF:

0.391

AC:

5978

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.472

AC:

1638

AN:

3468

East Asian (EAS)

AF:

0.830

AC:

4277

AN:

5156

South Asian (SAS)

AF:

0.445

AC:

2142

AN:

4812

European-Finnish (FIN)

AF:

0.299

AC:

3168

AN:

10580

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.363

AC:

24636

AN:

67958

Other (OTH)

AF:

0.465

AC:

982

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1861

3721

5582

7442

9303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.389

Hom.:

51332

Bravo

AF:

0.443

Asia WGS

AF:

0.632

AC:

2196

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.1

(source)

DANN

Benign

0.48

PhyloP100

0.091

Mutation Taster

=100/0

polymorphism (auto)

(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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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