NM_005391.5:c.336G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005391.5(PDK3):c.336G>C(p.Leu112Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,200,497 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000044 ( 0 hom. 15 hem. )

Consequence

PDK3
NM_005391.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.465

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, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

PDK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant X-24503342-G-C is Benign according to our data. Variant chrX-24503342-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 474052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.465 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	NM_005391.5	MANE Select	c.336G>C	p.Leu112Leu	synonymous	Exon 4 of 11	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.336G>C	p.Leu112Leu	synonymous	Exon 4 of 12	NP_001135858.1	Q15120-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDK3	ENST00000379162.9	TSL:1 MANE Select	c.336G>C	p.Leu112Leu	synonymous	Exon 4 of 11	ENSP00000368460.4	Q15120-1
PDK3	ENST00000568479.2	TSL:6	c.336G>C	p.Leu112Leu	synonymous	Exon 4 of 12	ENSP00000498864.1	Q15120-2
PDK3	ENST00000862654.1		c.336G>C	p.Leu112Leu	synonymous	Exon 4 of 10	ENSP00000532713.1

Frequencies

GnomAD3 genomes

AF:

0.0000802

AC:

AN:

112239

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000131

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000236

AC:

AN:

169253

AF XY:

0.0000182

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:

0.0000645

Gnomad NFE exome

AF:

0.0000389

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000441

AC:

AN:

1088258

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

354690

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26039

American (AMR)

AF:

0.00

AC:

AN:

33923

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18980

East Asian (EAS)

AF:

0.00

AC:

AN:

29942

South Asian (SAS)

AF:

0.00

AC:

AN:

52095

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4085

European-Non Finnish (NFE)

AF:

0.0000538

AC:

AN:

837146

Other (OTH)

AF:

0.0000437

AC:

AN:

45728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000802

AC:

AN:

112239

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34391

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30910

American (AMR)

AF:

0.00

AC:

AN:

10562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3603

South Asian (SAS)

AF:

0.00

AC:

AN:

2703

European-Finnish (FIN)

AF:

0.000164

AC:

AN:

6083

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000131

AC:

AN:

53295

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease X-linked dominant 6 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

4.7

(source)

DANN

Benign

0.70

PhyloP100

0.47

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over