chr19-7631476-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001171155.2(PET100):c.142C>T(p.Gln48*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,810 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_001171155.2 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 |
---|---|---|---|---|---|---|---|---|
PET100 | NM_001171155.2 | c.142C>T | p.Gln48* | stop_gained | Exon 4 of 4 | ENST00000594797.6 | NP_001164626.1 | |
STXBP2 | NM_001414484.1 | c.-60+630C>T | intron_variant | Intron 3 of 20 | NP_001401413.1 | |||
PET100 | NR_033242.2 | n.273C>T | non_coding_transcript_exon_variant | Exon 5 of 5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PET100 | ENST00000594797.6 | c.142C>T | p.Gln48* | stop_gained | Exon 4 of 4 | 1 | NM_001171155.2 | ENSP00000470539.1 | ||
ENSG00000268400 | ENST00000698368.1 | n.114+817C>T | intron_variant | Intron 2 of 19 | ENSP00000513686.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000725 AC: 1AN: 137842Hom.: 0 AF XY: 0.0000135 AC XY: 1AN XY: 74274
GnomAD4 exome AF: 0.00000145 AC: 2AN: 1383810Hom.: 0 Cov.: 32 AF XY: 0.00000293 AC XY: 2AN XY: 682842
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Mitochondrial complex 4 deficiency, nuclear type 12 Pathogenic:2
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This variant is interpreted as Likely pathogenic for Mitochondrial complex IV deficiency, nuclear type 12, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants (PM4); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate). -
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Variant summary: PET100 c.142C>T (p.Gln48X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a known mechanisms for disease. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 26 amino acids of the protein. The variant allele was found at a frequency of 7.3e-06 in 137842 control chromosomes (i.e., 1 heterozygote; gnomAD v2 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.142C>T has been reported in the literature in at least one homozygous individual affected with Cytochrome-c oxidase deficiency disease (e.g., Olahova_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% complex IV activity in homozygous patient muscle tissue and fibroblasts (e.g., Olahova_2015). The following publication was ascertained in the context of this evaluation (PMID: 25293719). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Congenital lactic acidosis;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at