chr11-34916458-AT-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001135024.2(PDHX):c.-48del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,462,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000023 ( 0 hom. )
Consequence
PDHX
NM_001135024.2 5_prime_UTR
NM_001135024.2 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.04
Genes affected
PDHX (HGNC:21350): (pyruvate dehydrogenase complex component X) The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to Krebs cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC eventually leads to cirrhosis and liver failure. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-34916458-AT-A is Pathogenic according to our data. Variant chr11-34916458-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 590822.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PDHX | NM_001135024.2 | c.-48del | 5_prime_UTR_variant | 1/11 | NP_001128496.2 | |||
PDHX | XM_011520390.2 | c.-21+521del | intron_variant | XP_011518692.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PDHX | ENST00000448838.8 | c.-48del | 5_prime_UTR_variant | 1/11 | 5 | ENSP00000389404 | ||||
PDHX | ENST00000533550.5 | c.-21+521del | intron_variant | 4 | ENSP00000431281 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151416Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000257 AC: 2AN: 77966Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 40496
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GnomAD4 exome AF: 0.00000229 AC: 3AN: 1311322Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0AN XY: 638810
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151416Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2AN XY: 73948
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1
Likely pathogenic, no assertion criteria provided | curation | SingHealth Duke-NUS Institute of Precision Medicine | Jun 07, 2017 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at