NM_005391.5:c.282T>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.282T>C(p.Tyr94Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,152,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 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 0.000092 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000072 ( 0 hom. 29 hem. )

Consequence

PDK3
NM_005391.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.172

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:

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=-0.6).

BP6

Variant X-24498862-T-C is Benign according to our data. Variant chrX-24498862-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.172 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK3	NM_005391.5 link	c.282T>C	p.Tyr94Tyr	synonymous_variant	Exon 3 of 11	ENST00000379162.9	NP_005382.1	Q15120-1
PDK3	NM_001142386.3 link	c.282T>C	p.Tyr94Tyr	synonymous_variant	Exon 3 of 12		NP_001135858.1	Q15120-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDK3	ENST00000379162.9 link	c.282T>C	p.Tyr94Tyr	synonymous_variant	Exon 3 of 11	1	NM_005391.5	ENSP00000368460.4	Q15120-1
PDK3	ENST00000568479.2 link	c.282T>C	p.Tyr94Tyr	synonymous_variant	Exon 3 of 12	6		ENSP00000498864.1	Q15120-2
PDK3	ENST00000493226.2 link	n.494T>C		non_coding_transcript_exon_variant	Exon 3 of 3	5
PDK3	ENST00000648777.1 link	n.282T>C		non_coding_transcript_exon_variant	Exon 3 of 12			ENSP00000497727.1	Q15120-1

Frequencies

GnomAD3 genomes

AF:

0.0000916

AC:

AN:

109179

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00345

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000154

AC:

AN:

156082

AF XY:

0.000218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00362

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000719

AC:

AN:

1043708

Hom.:

Cov.:

AF XY:

0.0000893

AC XY:

AN XY:

324814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24013

American (AMR)

AF:

0.00

AC:

AN:

29715

Ashkenazi Jewish (ASJ)

AF:

0.00321

AC:

AN:

18364

East Asian (EAS)

AF:

0.00

AC:

AN:

29316

South Asian (SAS)

AF:

0.00

AC:

AN:

48830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3764

European-Non Finnish (NFE)

AF:

0.0000124

AC:

AN:

805705

Other (OTH)

AF:

0.000137

AC:

AN:

43927

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000916

AC:

AN:

109179

Hom.:

Cov.:

AF XY:

0.0000952

AC XY:

AN XY:

31513

show subpopulations

African (AFR)

AF:

0.0000334

AC:

AN:

29966

American (AMR)

AF:

0.00

AC:

AN:

10135

Ashkenazi Jewish (ASJ)

AF:

0.00345

AC:

AN:

2608

East Asian (EAS)

AF:

0.00

AC:

AN:

3512

South Asian (SAS)

AF:

0.00

AC:

AN:

2523

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52514

Other (OTH)

AF:

0.00

AC:

AN:

1470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000609

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 11, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease X-linked dominant 6

Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.3

(source)

DANN

Benign

0.42

PhyloP100

0.17

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over