chr11-34995002-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003477.3(PDHX):c.1336C>T(p.Arg446*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_003477.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PDHX | NM_003477.3 | c.1336C>T | p.Arg446* | stop_gained | Exon 11 of 11 | ENST00000227868.9 | NP_003468.2 | |
PDHX | NM_001135024.2 | c.1156C>T | p.Arg386* | stop_gained | Exon 11 of 11 | NP_001128496.2 | ||
PDHX | NM_001166158.2 | c.655C>T | p.Arg219* | stop_gained | Exon 6 of 6 | NP_001159630.1 | ||
PDHX | XM_011520390.2 | c.1156C>T | p.Arg386* | stop_gained | Exon 11 of 11 | XP_011518692.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250988Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135634
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461744Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727172
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E3-binding protein deficiency Pathogenic:5
PVS1, PS4_mod, PM2- The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 162202). -
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Criteria applied: PVS1_STR,PM3_STR,PM2_SUP,PP4 -
not provided Pathogenic:3
PDHX: PM3:Strong, PVS1:Strong, PM2, PP4 -
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This sequence change creates a premature translational stop signal (p.Arg446*) in the PDHX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the PDHX protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of pyruvate dehydrogenase complex deficiency (PMID: 16904023, 25087164). It is commonly reported in individuals of Roma ancestry (PMID: 25087164). This variant is also known as R466X. ClinVar contains an entry for this variant (Variation ID: 162202). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at