X-24465434-T-C

Position:

• chrX-24465434-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005391.5(PDK3):​c.-22T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 1,145,267 control chromosomes in the GnomAD database, including 3,866 homozygotes. There are 13,566 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1637 hom., 4444 hem., cov: 24)
  • Exomes 𝑓: 0.028 (2229 hom. 9122 hem.)
• Consequence: PDK3 NM_005391.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0440

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-24465434-T-C is Benign according to our data. Variant chrX-24465434-T-C is described in ClinVar as [Benign]. Clinvar id is 138667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.-22T>C		5_prime_UTR_variant	1/11	ENST00000379162.9
PDK3	NM_001142386.3	c.-22T>C		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.-22T>C		5_prime_UTR_variant	1/11	1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.-22T>C		5_prime_UTR_variant	1/12
PDK3	ENST00000493226.2	n.191T>C		non_coding_transcript_exon_variant	1/3	5
PDK3	ENST00000648777.1	c.-22T>C		5_prime_UTR_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.128 AC: 14337 AN: 112191 Hom.: 1637 Cov.: 24 AF XY: 0.128 AC XY: 4438 AN XY: 34549

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0466

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0834 AC: 10571 AN: 126752 Hom.: 943 AF XY: 0.0734 AC XY: 2606 AN XY: 35482

Gnomad AFR exome AF: 0.405

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.0541

GnomAD4 exome AF: 0.0275 AC: 28442 AN: 1033031 Hom.: 2229 Cov.: 21 AF XY: 0.0289 AC XY: 9122 AN XY: 315987

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.0976

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.0498

GnomAD4 genome AF: 0.128 AC: 14343 AN: 112236 Hom.: 1637 Cov.: 24 AF XY: 0.128 AC XY: 4444 AN XY: 34604

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00323

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0508 Hom.: 494

Bravo AF: 0.147

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 23, 2014

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.2
DANN	Benign	0.70

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: rs72623011; hg19: chrX-24483551;