rs201754585
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000284.4(PDHA1):c.604-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,209,772 control chromosomes in the GnomAD database, including 7 homozygotes. There are 707 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.00082 ( 1 hom., 35 hem., cov: 24)
Exomes 𝑓: 0.0013 ( 6 hom. 672 hem. )
Consequence
PDHA1
NM_000284.4 splice_polypyrimidine_tract, intron
NM_000284.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001065
2
Clinical Significance
Conservation
PhyloP100: -1.05
Genes affected
PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) 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), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
?
Variant X-19355339-C-T is Benign according to our data. Variant chrX-19355339-C-T is described in ClinVar as [Benign]. Clinvar id is 214930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-19355339-C-T is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000824 (93/112893) while in subpopulation SAS AF= 0.0109 (30/2759). AF 95% confidence interval is 0.00783. There are 1 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd4 at 35 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHA1 | NM_000284.4 | c.604-10C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000422285.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHA1 | ENST00000422285.7 | c.604-10C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000284.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000824 AC: 93AN: 112839Hom.: 1 Cov.: 24 AF XY: 0.00100 AC XY: 35AN XY: 34989
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GnomAD3 exomes AF: 0.00209 AC: 383AN: 183357Hom.: 0 AF XY: 0.00296 AC XY: 201AN XY: 67803
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GnomAD4 exome AF: 0.00126 AC: 1385AN: 1096879Hom.: 6 Cov.: 31 AF XY: 0.00185 AC XY: 672AN XY: 362297
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GnomAD4 genome ? AF: 0.000824 AC: 93AN: 112893Hom.: 1 Cov.: 24 AF XY: 0.000998 AC XY: 35AN XY: 35053
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 28, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Pyruvate dehydrogenase E1-alpha deficiency Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at