rs746261967

Variant names:

• chrX-24533934-T-C
• rs746261967
• NM_005391.5:c.1083T>C
• PDK3 p.Leu361Leu

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005391.5(PDK3):​c.1083T>C​(p.Leu361Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000835 in 1,198,265 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000091 (0 hom. 37 hem.)
• Consequence: PDK3 NM_005391.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-24533934-T-C is Benign according to our data. Variant chrX-24533934-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 541113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 37 XL gene

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.1083T>C	p.Leu361Leu	synonymous	Exon 11 of 11	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.1083T>C	p.Leu361Leu	synonymous	Exon 11 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.1083T>C	p.Leu361Leu	synonymous	Exon 11 of 11	ENSP00000368460.4	Q15120-1
	PDK3	ENST00000568479.2	TSL:6	c.1083T>C	p.Leu361Leu	synonymous	Exon 11 of 12	ENSP00000498864.1	Q15120-2
	PDK3	ENST00000862654.1		c.972T>C	p.Leu324Leu	synonymous	Exon 10 of 10	ENSP00000532713.1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112226 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000170 AC: 3 AN: 176309 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000377

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000912 AC: 99 AN: 1086039 Hom.: 0 Cov.: 27 AF XY: 0.000105 AC XY: 37 AN XY: 352323

African (AFR) AF: 0.00 AC: 0 AN: 26157

American (AMR) AF: 0.00 AC: 0 AN: 34320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19070

East Asian (EAS) AF: 0.00 AC: 0 AN: 30093

South Asian (SAS) AF: 0.00 AC: 0 AN: 52467

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40321

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4063

European-Non Finnish (NFE) AF: 0.000116 AC: 97 AN: 833949

Other (OTH) AF: 0.0000439 AC: 2 AN: 45599

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112226 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34370

African (AFR) AF: 0.00 AC: 0 AN: 30854

American (AMR) AF: 0.00 AC: 0 AN: 10557

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3617

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53310

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease X-linked dominant 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.5
DANN	Benign	0.72
PhyloP100		1.5

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746261967;

hg19: chrX-24552051;