X-24465826-G-C

Variant names:

• chrX-24465826-G-C
• rs7877946
• NM_005391.5:c.106+265G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

PDK3 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 6

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000295515 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005391.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	NM_005391.5	MANE Select	c.106+265G>C		intron	N/A	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.106+265G>C		intron	N/A	NP_001135858.1	Q15120-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	ENST00000379162.9	TSL:1 MANE Select	c.106+265G>C		intron	N/A	ENSP00000368460.4	Q15120-1
	PDK3	ENST00000568479.2	TSL:6	c.106+265G>C		intron	N/A	ENSP00000498864.1	Q15120-2
	PDK3	ENST00000862654.1		c.106+265G>C		intron	N/A	ENSP00000532713.1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 48121 AN: 110391 Hom.: 8113 Cov.: 22

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

African (AFR) AF: 0.623 AC: 18874 AN: 30303

American (AMR) AF: 0.377 AC: 3977 AN: 10544

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 886 AN: 2644

East Asian (EAS) AF: 0.306 AC: 1061 AN: 3462

South Asian (SAS) AF: 0.562 AC: 1494 AN: 2659

European-Finnish (FIN) AF: 0.306 AC: 1737 AN: 5668

Middle Eastern (MID) AF: 0.452 AC: 94 AN: 208

European-Non Finnish (NFE) AF: 0.363 AC: 19133 AN: 52774

Other (OTH) AF: 0.423 AC: 637 AN: 1505

Alfa AF: 0.199 Hom.: 851

Bravo AF: 0.446

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.62
PhyloP100		-0.036
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7877946; hg19: chrX-24483943;