X-24465506-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005391.5(PDK3):c.51G>C(p.Glu17Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,208,786 control chromosomes in the GnomAD database, including 4 homozygotes. There are 319 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E17Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00025 ( 1 hom., 15 hem., cov: 25)

Exomes 𝑓: 0.00047 ( 3 hom. 304 hem. )

Consequence

PDK3
NM_005391.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.04

Publications

0 publications found

Variant links:

Genes affected

PDK3 (HGNC:8811): (pyruvate dehydrogenase kinase 3) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the three pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

PDK3 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 6
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

PDK3 links:

ENSG00000295515 (HGNC:):

ENSG00000295515 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007254839).

BP6

Variant X-24465506-G-C is Benign according to our data. Variant chrX-24465506-G-C is described in ClinVar as Benign. ClinVar VariationId is 474053.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 15 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005391.5. 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
	PDK3	NM_005391.5	MANE Select	c.51G>C	p.Glu17Asp	missense	Exon 1 of 11	NP_005382.1
	PDK3	NM_001142386.3		c.51G>C	p.Glu17Asp	missense	Exon 1 of 12	NP_001135858.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDK3	ENST00000379162.9	TSL:1 MANE Select	c.51G>C	p.Glu17Asp	missense	Exon 1 of 11	ENSP00000368460.4
PDK3	ENST00000568479.2	TSL:6	c.51G>C	p.Glu17Asp	missense	Exon 1 of 12	ENSP00000498864.1
PDK3	ENST00000493226.2	TSL:5	n.263G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000247

AC:

AN:

113397

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00944

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000651

GnomAD2 exomes

AF:

0.000845

AC:

149

AN:

176389

AF XY:

0.00136

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:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000471

AC:

516

AN:

1095339

Hom.:

Cov.:

AF XY:

0.000842

AC XY:

304

AN XY:

361061

show subpopulations

African (AFR)

AF:

0.0000760

AC:

AN:

26327

American (AMR)

AF:

0.00

AC:

AN:

35156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19343

East Asian (EAS)

AF:

0.00

AC:

AN:

30157

South Asian (SAS)

AF:

0.00904

AC:

488

AN:

54002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40189

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00000595

AC:

AN:

840069

Other (OTH)

AF:

0.000457

AC:

AN:

45966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000247

AC:

AN:

113447

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

AN XY:

35601

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31411

American (AMR)

AF:

0.00

AC:

AN:

10918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00947

AC:

AN:

2852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53286

Other (OTH)

AF:

0.000643

AC:

AN:

1556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.00120

AC:

146

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6

Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDK3-related disorder

Benign:1

May 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.020

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.91

REVEL

Benign

0.078

Sift

Benign

0.84

Sift4G

Benign

0.86

Polyphen

0.0

Vest4

0.18

MutPred

0.35

Loss of helix (P = 0.0558)

MVP

0.52

MPC

0.90

ClinPred

0.015

GERP RS

3.2

PromoterAI

0.054

Neutral

(source)

Varity_R

0.36

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over