chrX-24498906-T-C

Variant names:

• chrX-24498906-T-C
• rs748960946
• NM_005391.5:c.320+6T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005391.5(PDK3):​c.320+6T>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,057,127 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000038 (0 hom. 14 hem.)
• Consequence: PDK3 NM_005391.5 splice_region, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.65
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Hemizygotes in GnomAdExome4 at 14 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.320+6T>C		splice_region intron	N/A	NP_005382.1	Q15120-1
	PDK3	NM_001142386.3		c.320+6T>C		splice_region 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.320+6T>C		splice_region intron	N/A	ENSP00000368460.4	Q15120-1
	PDK3	ENST00000568479.2	TSL:6	c.320+6T>C		splice_region intron	N/A	ENSP00000498864.1	Q15120-2
	PDK3	ENST00000862654.1		c.320+6T>C		splice_region intron	N/A	ENSP00000532713.1

Frequencies

GnomAD3 genomes AF: 0.00000907 AC: 1 AN: 110195 Hom.: 0 Cov.: 21

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: 0.0000190

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000212 AC: 3 AN: 141405 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000621

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000293

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000380 AC: 36 AN: 946932 Hom.: 0 Cov.: 17 AF XY: 0.0000538 AC XY: 14 AN XY: 260346

African (AFR) AF: 0.00 AC: 0 AN: 21594

American (AMR) AF: 0.00 AC: 0 AN: 23764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16787

East Asian (EAS) AF: 0.00 AC: 0 AN: 28316

South Asian (SAS) AF: 0.00 AC: 0 AN: 43438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39231

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3254

European-Non Finnish (NFE) AF: 0.0000479 AC: 35 AN: 730032

Other (OTH) AF: 0.0000247 AC: 1 AN: 40516

GnomAD4 genome AF: 0.00000907 AC: 1 AN: 110195 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32471

African (AFR) AF: 0.00 AC: 0 AN: 30268

American (AMR) AF: 0.00 AC: 0 AN: 10304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52722

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.0000877 Hom.: 1

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		7.6
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: 34
DS_DL_spliceai		0.55		Position offset: -6

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

Other links and lift over

dbSNP: rs748960946; hg19: chrX-24517023;