rs141326782

Positions:

chrX-24539144-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001142386.3(PDK3):c.1228A>C(p.Lys410Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,122,899 control chromosomes in the GnomAD database, including 53 homozygotes. There are 791 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., 404 hem., cov: 23)

Exomes 𝑓: 0.0016 ( 28 hom. 387 hem. )

Consequence

PDK3
NM_001142386.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.75

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:

PDK3 (HGNC:):

PDK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003305912).

BP6

Variant X-24539144-A-C is Benign according to our data. Variant chrX-24539144-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 474050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-24539144-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (1499/112468) while in subpopulation AFR AF= 0.0453 (1400/30915). AF 95% confidence interval is 0.0433. There are 25 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDK3	NM_001142386.3 linkuse as main transcript	c.1228A>C	p.Lys410Gln	missense_variant	12/12		NP_001135858.1	Q15120-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
PDK3	ENST00000568479.2 linkuse as main transcript	c.1228A>C	p.Lys410Gln	missense_variant	12/12	6	ENSP00000498864.1	Q15120-2
PDK3	ENST00000648777.1 linkuse as main transcript	n.*595A>C		non_coding_transcript_exon_variant	12/12		ENSP00000497727.1	Q15120-1
PDK3	ENST00000688031.1 linkuse as main transcript	n.1356A>C		non_coding_transcript_exon_variant	6/6
PDK3	ENST00000648777.1 linkuse as main transcript	n.*595A>C		3_prime_UTR_variant	12/12		ENSP00000497727.1	Q15120-1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

1494

AN:

112417

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

400

AN XY:

34591

show subpopulations

Gnomad AFR

AF:

0.0452

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00591

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000300

Gnomad OTH

AF:

0.0132

GnomAD3 exomes

AF:

0.00330

AC:

365

AN:

110595

Hom.:

AF XY:

0.00237

AC XY:

AN XY:

38445

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.00236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000728

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000347

Gnomad OTH exome

AF:

0.00317

GnomAD4 exome

AF:

0.00161

AC:

1622

AN:

1010431

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

387

AN XY:

311427

show subpopulations

Gnomad4 AFR exome

AF:

0.0499

Gnomad4 AMR exome

AF:

0.00298

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000188

Gnomad4 OTH exome

AF:

0.00412

GnomAD4 genome

AF:

0.0133

AC:

1499

AN:

112468

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

404

AN XY:

34652

show subpopulations

Gnomad4 AFR

AF:

0.0453

Gnomad4 AMR

AF:

0.00591

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000300

Gnomad4 OTH

AF:

0.0130

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.0163

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00470

AC:

104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.97

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.18

REVEL

Benign

0.036

Sift

Uncertain

0.017

Sift4G

Benign

0.35

Vest4

0.091

MVP

0.32

MPC

1.1

ClinPred

0.0084

GERP RS

3.9

Splicing

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