chrX-24465288-T-G

Variant names:

• chrX-24465288-T-G
• rs7891330
• NM_005391.5:c.-168T>G

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PDK3	NM_005391.5	c.-168T>G		5_prime_UTR_variant	Exon 1 of 11	ENST00000379162.9	NP_005382.1
PDK3	NM_001142386.3	c.-168T>G		5_prime_UTR_variant	Exon 1 of 12		NP_001135858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDK3	ENST00000379162	c.-168T>G		5_prime_UTR_variant	Exon 1 of 11	1	NM_005391.5	ENSP00000368460.4

Frequencies

GnomAD3 genomes AF: 0.475 AC: 52248 AN: 109944 Hom.: 9346 Cov.: 25

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 AC: 3078 AN: 4617

Gnomad4 AMR exome AF: 0.483 AC: 2167 AN: 4489

Gnomad4 ASJ exome AF: 0.357 AC: 2041 AN: 5721

Gnomad4 EAS exome AF: 0.401 AC: 5973 AN: 14897

Gnomad4 SAS exome AF: 0.457 AC: 2133 AN: 4667

Gnomad4 FIN exome AF: 0.368 AC: 6024 AN: 16364

Gnomad4 NFE exome AF: 0.356 AC: 42580 AN: 119590

Gnomad4 Remaining exome AF: 0.406 AC: 4714 AN: 11616

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 AC: 0.685724 AN: 0.685724

Gnomad4 AMR AF: 0.475 AC: 0.474755 AN: 0.474755

Gnomad4 ASJ AF: 0.349 AC: 0.348756 AN: 0.348756

Gnomad4 EAS AF: 0.365 AC: 0.365351 AN: 0.365351

Gnomad4 SAS AF: 0.575 AC: 0.574576 AN: 0.574576

Gnomad4 FIN AF: 0.384 AC: 0.384154 AN: 0.384154

Gnomad4 NFE AF: 0.370 AC: 0.370496 AN: 0.370496

Gnomad4 OTH AF: 0.455 AC: 0.455268 AN: 0.455268

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

Mar 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.83
Mutation Taster		=300/0	polymorphism (auto)

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;