Genetic Variant PDK4:p.Asn324Asp (chr7-95587429-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002612.4(PDK4):c.970A>G(p.Asn324Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,439,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N324H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

PDK4
NM_002612.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24187517).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002612.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK4	NM_002612.4	MANE Select	c.970A>G	p.Asn324Asp	missense	Exon 9 of 11	NP_002603.1	A4D1H4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDK4	ENST00000005178.6	TSL:1 MANE Select	c.970A>G	p.Asn324Asp	missense	Exon 9 of 11	ENSP00000005178.5	Q16654
PDK4	ENST00000886049.1		c.970A>G	p.Asn324Asp	missense	Exon 10 of 12	ENSP00000556108.1
PDK4	ENST00000886050.1		c.964A>G	p.Asn322Asp	missense	Exon 9 of 11	ENSP00000556109.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251280

AF XY:

0.0000147

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000347

AC:

AN:

1439504

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

717640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1091602

Other (OTH)

AF:

0.00

AC:

AN:

59658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000312

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.017

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.29

PhyloP100

2.3

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.0

REVEL

Benign

0.12

Sift

Benign

0.63

Sift4G

Benign

0.69

Polyphen

0.0010

Vest4

0.53

MutPred

0.28

Gain of disorder (P = 0.1471)

MVP

0.50

MPC

0.11

ClinPred

0.32

GERP RS

5.8

Varity_R

0.68

gMVP

0.50

Mutation Taster

=89/11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over