X-24465305-T-TGCTGCTGCG

Position:

• chrX-24465305-T-TGCTGCTGCG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005391.5(PDK3):​c.-148_-140dup 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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDK3	NM_005391.5	c.-148_-140dup		5_prime_UTR_variant	1/11	ENST00000379162.9
PDK3	NM_001142386.3	c.-148_-140dup		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDK3	ENST00000379162.9	c.-148_-140dup		5_prime_UTR_variant	1/11	1	NM_005391.5	P1
PDK3	ENST00000568479.2	c.-148_-140dup		5_prime_UTR_variant	1/12
PDK3	ENST00000493226.2	n.65_73dup		non_coding_transcript_exon_variant	1/3	5
PDK3	ENST00000648777.1	c.-148_-140dup		5_prime_UTR_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 6319 AN: 112441 Hom.: 161 Cov.: 22 AF XY: 0.0570 AC XY: 1980 AN XY: 34759

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

Gnomad4 AFR exome AF: 0.00819

Gnomad4 AMR exome AF: 0.0763

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0268

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.0670

Gnomad4 OTH exome AF: 0.0634

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

Gnomad4 AFR AF: 0.00856

Gnomad4 AMR AF: 0.0773

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.0207

Gnomad4 SAS AF: 0.0194

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.0718

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0240 Hom.: 100

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs764167975; hg19: chrX-24483422;