X-24465288-T-G

Position:

• chrX-24465288-T-G

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.-168T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 292,778 control chromosomes in the GnomAD database, including 18,751 homozygotes. There are 36,780 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (9346 hom., 15797 hem., cov: 25)
  • Exomes 𝑓: 0.38 (9405 hom. 20983 hem.)
• Consequence: PDK3 NM_005391.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0580

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=-0.76).
• BP6: Variant X-24465288-T-G is Benign according to our data. Variant chrX-24465288-T-G is described in ClinVar as [Benign]. Clinvar id is 1293371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.-168T>G		5_prime_UTR_variant	1/11	ENST00000379162.9
PDK3	NM_001142386.3	c.-168T>G		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.-168T>G		5_prime_UTR_variant	1/11	1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.-168T>G		5_prime_UTR_variant	1/12
PDK3	ENST00000493226.2	n.45T>G		non_coding_transcript_exon_variant	1/3	5
PDK3	ENST00000648777.1	c.-168T>G		5_prime_UTR_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.475 AC: 52248 AN: 109944 Hom.: 9346 Cov.: 25 AF XY: 0.485 AC XY: 15754 AN XY: 32500

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.485

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.378 AC: 69053 AN: 182787 Hom.: 9405 Cov.: 3 AF XY: 0.382 AC XY: 20983 AN XY: 54955

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.457

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.475 AC: 52288 AN: 109991 Hom.: 9346 Cov.: 25 AF XY: 0.485 AC XY: 15797 AN XY: 32557

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.475

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.575

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.455

Alfa AF: 0.247 Hom.: 1143

Bravo AF: 0.480

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.83

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: rs7891330; hg19: chrX-24483405;