X-24465826-G-C

Position:

• chrX-24465826-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005391.5(PDK3):​c.106+265G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 110,443 control chromosomes in the GnomAD database, including 8,110 homozygotes. There are 13,834 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (8110 hom., 13834 hem., cov: 22)
• Consequence: PDK3 NM_005391.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0360

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-24465826-G-C is Benign according to our data. Variant chrX-24465826-G-C is described in ClinVar as [Benign]. Clinvar id is 1182652.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.106+265G>C		intron_variant		ENST00000379162.9
PDK3	NM_001142386.3	c.106+265G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.106+265G>C		intron_variant		1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.106+265G>C		intron_variant
PDK3	ENST00000648777.1	c.106+265G>C		intron_variant, NMD_transcript_variant
PDK3	ENST00000493226.2	n.318+265G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.436 AC: 48121 AN: 110391 Hom.: 8113 Cov.: 22 AF XY: 0.422 AC XY: 13801 AN XY: 32667

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.470

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.419

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.436 AC: 48143 AN: 110443 Hom.: 8110 Cov.: 22 AF XY: 0.423 AC XY: 13834 AN XY: 32731

Gnomad4 AFR AF: 0.623

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.335

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.562

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.423

Alfa AF: 0.199 Hom.: 851

Bravo AF: 0.446

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7877946; hg19: chrX-24483943;