rs2229137
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BA1BS2
This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.844A>C; p. M282L variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121220/MONDO:0019169/014
Frequency
Consequence
NM_000284.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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PDHA1 | NM_000284.4 | c.844A>C | p.Met282Leu | missense_variant | Exon 9 of 11 | ENST00000422285.7 | NP_000275.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00953 AC: 1065AN: 111782Hom.: 86 Cov.: 23 AF XY: 0.0104 AC XY: 353AN XY: 33974
GnomAD3 exomes AF: 0.0214 AC: 3930AN: 183510Hom.: 331 AF XY: 0.0191 AC XY: 1298AN XY: 67940
GnomAD4 exome AF: 0.00789 AC: 8643AN: 1095835Hom.: 623 Cov.: 28 AF XY: 0.00797 AC XY: 2880AN XY: 361269
GnomAD4 genome AF: 0.00950 AC: 1063AN: 111837Hom.: 85 Cov.: 23 AF XY: 0.0104 AC XY: 355AN XY: 34039
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1Benign:2
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
not specified Benign:3
Variant summary: PDHA1 c.844A>C (p.Met282Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.021 in 183510 control chromosomes, predominantly at a frequency of 0.26 within the East Asian subpopulation in the gnomAD database, including 329 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 831999.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in PDHA1 causing Pyruvate Dehydrogenase Deficiency phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, all but one classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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. -
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Pyruvate dehydrogenase complex deficiency Benign:2
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The allele frequency of the c.844A>C (p.M282L) variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021. -
not provided Benign:2
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Inborn genetic diseases Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at