rs138321172

Positions:

• chrX-24503382-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005391.5(PDK3):​c.376A>G​(p.Met126Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,202,481 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 741 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 37 hem., cov: 23)
  • Exomes 𝑓: 0.0020 (0 hom. 704 hem.)
• Consequence: PDK3 NM_005391.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03498575).
• BP6: Variant X-24503382-A-G is Benign according to our data. Variant chrX-24503382-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382040.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chrX-24503382-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 37 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDK3	NM_005391.5	c.376A>G	p.Met126Val	missense_variant	4/11	ENST00000379162.9	NP_005382.1
PDK3	NM_001142386.3	c.376A>G	p.Met126Val	missense_variant	4/12		NP_001135858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDK3	ENST00000379162.9	c.376A>G	p.Met126Val	missense_variant	4/11	1	NM_005391.5	ENSP00000368460.4
PDK3	ENST00000568479.2	c.376A>G	p.Met126Val	missense_variant	4/12	6		ENSP00000498864.1
PDK3	ENST00000648777.1	n.376A>G		non_coding_transcript_exon_variant	4/12			ENSP00000497727.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 132 AN: 112194 Hom.: 0 Cov.: 23 AF XY: 0.00108 AC XY: 37 AN XY: 34338

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00197

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.00120 AC: 215 AN: 178817 Hom.: 0 AF XY: 0.00129 AC XY: 82 AN XY: 63477

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00113

Gnomad FIN exome AF: 0.00207

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.000912

GnomAD4 exome AF: 0.00202 AC: 2198 AN: 1090231 Hom.: 0 Cov.: 27 AF XY: 0.00198 AC XY: 704 AN XY: 355845

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00244

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00118 AC: 132 AN: 112250 Hom.: 0 Cov.: 23 AF XY: 0.00108 AC XY: 37 AN XY: 34404

Gnomad4 AFR AF: 0.000226

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00197

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.00173 Hom.: 79

Bravo AF: 0.00107

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00238 AC: 16

ExAC AF: 0.00122 AC: 148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2023	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2015	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. -

Charcot-Marie-Tooth disease X-linked dominant 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

PDK3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

This variant is classified as likely 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	0.23
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.29
Sift	Benign	0.080	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.93	P;.
Vest4		0.66
MVP		0.83
MPC		1.1
ClinPred		0.11	T
GERP RS		6.0
Varity_R		0.81

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

Other links and lift over

dbSNP: rs138321172; hg19: chrX-24521499;