X-24498821-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_005391.5(PDK3):c.249-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000021 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PDK3 NM_005391.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001216
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.439

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-24498821-C-T is Benign according to our data. Variant chrX-24498821-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474051.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.249-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000379162.9
PDK3	NM_001142386.3	c.249-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.249-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.249-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PDK3	ENST00000648777.1	c.249-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant
PDK3	ENST00000493226.2	n.461-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9 AN: 104141 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 28683 FAILED QC

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000437

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000213 AC: 19 AN: 891073 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 251493

Gnomad4 AFR exome AF: 0.0000499

Gnomad4 AMR exome AF: 0.000187

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000373

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000265

Gnomad4 NFE exome AF: 0.0000174

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000864 AC: 9 AN: 104176 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 28728

Gnomad4 AFR AF: 0.000105

Gnomad4 AMR AF: 0.000103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000437

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00420 Hom.: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	2.6
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs1231289510; hg19: chrX-24516938; COSMIC: COSV64792839;