X-24465305-T-TGCTGCTGCGGCTGCTGCG

Variant names:

• chrX-24465305-T-TGCTGCTGCGGCTGCTGCG
• rs764167975
• NM_005391.5:c.-140_-139insTGCTGCGGCTGCTGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005391.5(PDK3):​c.-140_-139insTGCTGCGGCTGCTGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 239,532 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000042 (0 hom. 0 hem.)
• Consequence: PDK3 NM_005391.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000295515 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.-140_-139insTGCTGCGGCTGCTGCGGC		5_prime_UTR	Exon 1 of 11	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.-140_-139insTGCTGCGGCTGCTGCGGC		5_prime_UTR	Exon 1 of 12	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.-140_-139insTGCTGCGGCTGCTGCGGC		5_prime_UTR	Exon 1 of 11	ENSP00000368460.4	Q15120-1
	PDK3	ENST00000568479.2	TSL:6	c.-140_-139insTGCTGCGGCTGCTGCGGC		5_prime_UTR	Exon 1 of 12	ENSP00000498864.1	Q15120-2
	PDK3	ENST00000862654.1		c.-140_-139insTGCTGCGGCTGCTGCGGC		5_prime_UTR	Exon 1 of 10	ENSP00000532713.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000417 AC: 1 AN: 239532 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 75244

African (AFR) AF: 0.00 AC: 0 AN: 5250

American (AMR) AF: 0.00 AC: 0 AN: 5298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6833

East Asian (EAS) AF: 0.00 AC: 0 AN: 16005

South Asian (SAS) AF: 0.00 AC: 0 AN: 13540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20889

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1008

European-Non Finnish (NFE) AF: 0.00000640 AC: 1 AN: 156354

Other (OTH) AF: 0.00 AC: 0 AN: 14355

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 100

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs764167975; hg19: chrX-24483422;