X-24486794-A-C

Position:

• chrX-24486794-A-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.107-7948A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 109,736 control chromosomes in the GnomAD database, including 9,533 homozygotes. There are 14,284 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (9533 hom., 14284 hem., cov: 22)
• Consequence: PDK3 NM_005391.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.06

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=-1.02).
• BP6: Variant X-24486794-A-C is Benign according to our data. Variant chrX-24486794-A-C is described in ClinVar as [Benign]. Clinvar id is 1599762.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.107-7948A>C		intron_variant		ENST00000379162.9
PDK3	NM_001142386.3	c.107-7948A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.107-7948A>C		intron_variant		1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.107-7948A>C		intron_variant
PDK3	ENST00000648777.1	c.107-7948A>C		intron_variant, NMD_transcript_variant
PDK3	ENST00000493226.2	n.319-7948A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.460 AC: 50405 AN: 109684 Hom.: 9534 Cov.: 22 AF XY: 0.445 AC XY: 14239 AN XY: 31998

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.460 AC: 50447 AN: 109736 Hom.: 9533 Cov.: 22 AF XY: 0.446 AC XY: 14284 AN XY: 32060

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.302

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.441

Alfa AF: 0.416 Hom.: 2885

Bravo AF: 0.474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.27
DANN	Benign	0.75

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: rs7060702; hg19: chrX-24504911;