X-24465506-G-C

Position:

chrX-24465506-G-C

Variant summary

Our verdict is Benign. Variant got -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. 12/18 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 474053.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-24465506-G-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5 linkuse as main transcript	c.51G>C	p.Glu17Asp	missense_variant	1/11	ENST00000379162.9
PDK3	NM_001142386.3 linkuse as main transcript	c.51G>C	p.Glu17Asp	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9 linkuse as main transcript	c.51G>C	p.Glu17Asp	missense_variant	1/11	1	NM_005391.5	P1	Q15120-1
PDK3	ENST00000568479.2 linkuse as main transcript	c.51G>C	p.Glu17Asp	missense_variant	1/12				Q15120-2
PDK3	ENST00000493226.2 linkuse as main transcript	n.263G>C		non_coding_transcript_exon_variant	1/3	5
PDK3	ENST00000648777.1 linkuse as main transcript	c.51G>C	p.Glu17Asp	missense_variant, NMD_transcript_variant	1/12				Q15120-1

Frequencies

GnomAD3 genomes

AF:

0.000247

AC:

AN:

113397

Hom.:

Cov.:

AF XY:

0.000422

AC XY:

AN XY:

35541

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

GnomAD3 exomes

AF:

0.000845

AC:

149

AN:

176389

Hom.:

AF XY:

0.00136

AC XY:

AN XY:

64079

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 SAS exome

AF:

0.00789

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

Gnomad4 AFR exome

AF:

0.0000760

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00904

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000595

Gnomad4 OTH exome

AF:

0.000457

GnomAD4 genome

AF:

0.000247

AC:

AN:

113447

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

AN XY:

35601

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00947

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000643

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2023

- -

PDK3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.020

T;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

.;D

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.91

N;N

REVEL

Benign

0.078

Sift

Benign

0.84

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0

B;.

Vest4

0.18

MutPred

0.35

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.52

MPC

0.90

ClinPred

0.015

GERP RS

3.2

Varity_R

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over