NM_001142386.3:c.1228A>C

Variant names:

• chrX-24539144-A-C
• rs141326782
• NM_001142386.3:c.1228A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 11/16 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.75
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 474050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142386.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	NM_001142386.3		c.1228A>C	p.Lys410Gln	missense	Exon 12 of 12	NP_001135858.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	ENST00000568479.2	TSL:6	c.1228A>C	p.Lys410Gln	missense	Exon 12 of 12	ENSP00000498864.1
	PDK3	ENST00000648777.1		n.*595A>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000497727.1
	PDK3	ENST00000688031.1		n.1356A>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 1494 AN: 112417 Hom.: 25 Cov.: 23

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

GnomAD2 exomes AF: 0.00330 AC: 365 AN: 110595 AF XY: 0.00237

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 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.: 28 Cov.: 21 AF XY: 0.00124 AC XY: 387 AN XY: 311427

African (AFR) AF: 0.0499 AC: 1200 AN: 24037

American (AMR) AF: 0.00298 AC: 82 AN: 27539

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18338

East Asian (EAS) AF: 0.00 AC: 0 AN: 26954

South Asian (SAS) AF: 0.000123 AC: 6 AN: 48683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37616

Middle Eastern (MID) AF: 0.00251 AC: 10 AN: 3987

European-Non Finnish (NFE) AF: 0.000188 AC: 147 AN: 780322

Other (OTH) AF: 0.00412 AC: 177 AN: 42955

GnomAD4 genome AF: 0.0133 AC: 1499 AN: 112468 Hom.: 25 Cov.: 23 AF XY: 0.0117 AC XY: 404 AN XY: 34652

African (AFR) AF: 0.0453 AC: 1400 AN: 30915

American (AMR) AF: 0.00591 AC: 63 AN: 10667

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000300 AC: 16 AN: 53304

Other (OTH) AF: 0.0130 AC: 20 AN: 1535

Alfa AF: 0.00445 Hom.: 179

Bravo AF: 0.0163

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00470 AC: 104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Dec 01, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.97
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.036
Sift	Uncertain	0.017	D
Sift4G	Benign	0.35	T
Vest4		0.091
MVP		0.32
MPC		1.1
ClinPred		0.0084	T
GERP RS		3.9
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141326782; hg19: chrX-24557261;