chrX-24465468-C-G

Variant names:

• chrX-24465468-C-G
• NM_005391.5:c.13C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005391.5(PDK3):​c.13C>G​(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,882 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: PDK3 NM_005391.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.403

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09368813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDK3	NM_005391.5	c.13C>G	p.Arg5Gly	missense_variant	Exon 1 of 11	ENST00000379162.9	NP_005382.1
PDK3	NM_001142386.3	c.13C>G	p.Arg5Gly	missense_variant	Exon 1 of 12		NP_001135858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK3	ENST00000379162.9	c.13C>G	p.Arg5Gly	missense_variant	Exon 1 of 11	1	NM_005391.5	ENSP00000368460.4
PDK3	ENST00000568479.2	c.13C>G	p.Arg5Gly	missense_variant	Exon 1 of 12	6		ENSP00000498864.1
PDK3	ENST00000493226.2	n.225C>G		non_coding_transcript_exon_variant	Exon 1 of 3	5
PDK3	ENST00000648777.1	n.13C>G		non_coding_transcript_exon_variant	Exon 1 of 12			ENSP00000497727.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090882 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 357968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.049	T;.
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.055
Sift	Benign	0.15	T;T
Sift4G	Benign	0.077	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.53		Loss of MoRF binding (P = 0.0386);Loss of MoRF binding (P = 0.0386);
MVP		0.25
MPC		1.2
ClinPred		0.11	T
GERP RS		1.4
Varity_R		0.10

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-24483585;