chrX-24465305-T-TGCTGCTGCG

Variant names:

• chrX-24465305-T-TGCTGCTGCG
• rs764167975
• NM_005391.5:c.-148_-140dupTGCTGCGGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005391.5(PDK3):​c.-148_-140dupTGCTGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 351,767 control chromosomes in the GnomAD database, including 637 homozygotes. There are 7,125 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (161 hom., 1981 hem., cov: 22)
  • Exomes 𝑓: 0.067 (476 hom. 5144 hem.)
• Consequence: PDK3 NM_005391.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-24465305-T-TGCTGCTGCG is Benign according to our data. Variant chrX-24465305-T-TGCTGCTGCG is described in ClinVar as Benign. ClinVar VariationId is 1292265.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0729 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.-148_-140dupTGCTGCGGC		5_prime_UTR	Exon 1 of 11	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.-148_-140dupTGCTGCGGC		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.-148_-140dupTGCTGCGGC		5_prime_UTR	Exon 1 of 11	ENSP00000368460.4	Q15120-1
	PDK3	ENST00000568479.2	TSL:6	c.-148_-140dupTGCTGCGGC		5_prime_UTR	Exon 1 of 12	ENSP00000498864.1	Q15120-2
	PDK3	ENST00000862654.1		c.-148_-140dupTGCTGCGGC		5_prime_UTR	Exon 1 of 10	ENSP00000532713.1

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 6319 AN: 112441 Hom.: 161 Cov.: 22

Gnomad AFR AF: 0.00855

Gnomad AMI AF: 0.0688

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0206

Gnomad SAS AF: 0.0194

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0427

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0703

GnomAD4 exome AF: 0.0674 AC: 16134 AN: 239282 Hom.: 476 Cov.: 3 AF XY: 0.0685 AC XY: 5144 AN XY: 75148

African (AFR) AF: 0.00819 AC: 43 AN: 5250

American (AMR) AF: 0.0763 AC: 404 AN: 5293

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 701 AN: 6822

East Asian (EAS) AF: 0.0268 AC: 429 AN: 15999

South Asian (SAS) AF: 0.0225 AC: 304 AN: 13528

European-Finnish (FIN) AF: 0.135 AC: 2805 AN: 20855

Middle Eastern (MID) AF: 0.0666 AC: 67 AN: 1006

European-Non Finnish (NFE) AF: 0.0670 AC: 10471 AN: 156183

Other (OTH) AF: 0.0634 AC: 910 AN: 14346

GnomAD4 genome AF: 0.0562 AC: 6320 AN: 112485 Hom.: 161 Cov.: 22 AF XY: 0.0569 AC XY: 1981 AN XY: 34813

African (AFR) AF: 0.00856 AC: 267 AN: 31176

American (AMR) AF: 0.0773 AC: 836 AN: 10820

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 295 AN: 2641

East Asian (EAS) AF: 0.0207 AC: 73 AN: 3524

South Asian (SAS) AF: 0.0194 AC: 55 AN: 2830

European-Finnish (FIN) AF: 0.136 AC: 824 AN: 6068

Middle Eastern (MID) AF: 0.0469 AC: 10 AN: 213

European-Non Finnish (NFE) AF: 0.0718 AC: 3807 AN: 53004

Other (OTH) AF: 0.0695 AC: 107 AN: 1540

Alfa AF: 0.0240 Hom.: 100

ClinVar

ClinVar submissions

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
PhyloP100		0.34
Mutation Taster		=300/0	polymorphism (auto)

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;