rs371137355

Positions:

• chrX-24465506-G-C
• chrX-24465506-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.04

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 -16 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_multiple_submitters_no_conflicts, 2 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	c.51G>C	p.Glu17Asp	missense_variant	1/11	ENST00000379162.9
PDK3	NM_001142386.3	c.51G>C	p.Glu17Asp	missense_variant	1/12

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000247 AC: 28 AN: 113397 Hom.: 1 Cov.: 25 AF XY: 0.000422 AC XY: 15 AN XY: 35541

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.: 1 AF XY: 0.00136 AC XY: 87 AN XY: 64079

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.: 3 Cov.: 28 AF XY: 0.000842 AC XY: 304 AN XY: 361061

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: 28 AN: 113447 Hom.: 1 Cov.: 25 AF XY: 0.000421 AC XY: 15 AN XY: 35601

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.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00120 AC: 146

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

- -

PDK3-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.020	T;.
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
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	T
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

Other links and lift over

dbSNP: rs371137355; hg19: chrX-24483623;