X-24539144-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142386.3(PDK3):​c.1228A>G​(p.Lys410Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000099 in 1,010,445 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K410Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.9e-7 (0 hom. 1 hem.)
• Consequence: PDK3 NM_001142386.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19301113).

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>G	p.Lys410Glu	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>G	p.Lys410Glu	missense	Exon 12 of 12	ENSP00000498864.1
	PDK3	ENST00000648777.1		n.*595A>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000497727.1
	PDK3	ENST00000688031.1		n.1356A>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.90e-7 AC: 1 AN: 1010445 Hom.: 0 Cov.: 21 AF XY: 0.00000321 AC XY: 1 AN XY: 311419

African (AFR) AF: 0.00 AC: 0 AN: 24057

American (AMR) AF: 0.00 AC: 0 AN: 27538

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

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

South Asian (SAS) AF: 0.0000205 AC: 1 AN: 48682

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3987

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 780318

Other (OTH) AF: 0.00 AC: 0 AN: 42955

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.088
Sift	Uncertain	0.010	D
Sift4G	Benign	0.22	T
Vest4		0.37
MutPred		0.23		Gain of ubiquitination at K405 (P = 0.028)
MVP		0.59
MPC		1.4
ClinPred		0.47	T
GERP RS		3.9
Mutation Taster		=97/3	polymorphism

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;