ENST00000523021.1:n.389-17352G>A

Variant names:

• chr8-93903875-G-A
• rs35820208
• ENST00000523021.1:n.389-17352G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000523021.1(PDP1):​n.389-17352G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 149,230 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.062 (340 hom., cov: 29)
• Consequence: PDP1 ENST00000523021.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 2 publications found

Genes affected

PDP1 (HGNC:9279): (pyruvate dehydrogenase phosphatase catalytic subunit 1) Pyruvate dehydrogenase (E1) is one of the three components (E1, E2, and E3) of the large pyruvate dehydrogenase complex. Pyruvate dehydrogenase kinases catalyze phosphorylation of serine residues of E1 to inactivate the E1 component and inhibit the complex. Pyruvate dehydrogenase phosphatases catalyze the dephosphorylation and activation of the E1 component to reverse the effects of pyruvate dehydrogenase kinases. Pyruvate dehydrogenase phosphatase is a heterodimer consisting of catalytic and regulatory subunits. Two catalytic subunits have been reported; one is predominantly expressed in skeletal muscle and another one is is much more abundant in the liver. The catalytic subunit, encoded by this gene, is the former, and belongs to the protein phosphatase 2C (PP2C) superfamily. Along with the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinases, this enzyme is located in the mitochondrial matrix. Mutation in this gene causes pyruvate dehydrogenase phosphatase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Jun 2009]

PDP1 Gene-Disease associations (from GenCC):

• pyruvate dehydrogenase phosphatase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDP1	ENST00000523021.1	n.389-17352G>A		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes AF: 0.0617 AC: 9196 AN: 149156 Hom.: 341 Cov.: 29

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.0775

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0616 AC: 9192 AN: 149230 Hom.: 340 Cov.: 29 AF XY: 0.0610 AC XY: 4429 AN XY: 72614

African (AFR) AF: 0.0440 AC: 1789 AN: 40648

American (AMR) AF: 0.0613 AC: 916 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 352 AN: 3454

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5052

South Asian (SAS) AF: 0.0543 AC: 256 AN: 4718

European-Finnish (FIN) AF: 0.0623 AC: 600 AN: 9636

Middle Eastern (MID) AF: 0.116 AC: 33 AN: 284

European-Non Finnish (NFE) AF: 0.0722 AC: 4875 AN: 67520

Other (OTH) AF: 0.0768 AC: 158 AN: 2056

Alfa AF: 0.0640 Hom.: 45

Bravo AF: 0.0614

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.68
PhyloP100		-1.6

Splicing

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

Other links and lift over

dbSNP: rs35820208; hg19: chr8-94916103;