chr19-7629836-G-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1_ModeratePM2PP5_Very_StrongBS1_Supporting
The NM_001171155.2(PET100):āc.3G>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000795 in 1,384,244 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 Pathogenic (ā ā ).
Frequency
Consequence
NM_001171155.2 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PET100 | NM_001171155.2 | c.3G>C | p.Met1? | start_lost | Exon 1 of 4 | ENST00000594797.6 | NP_001164626.1 | |
STXBP2 | NM_001414484.1 | c.-195G>C | 5_prime_UTR_variant | Exon 1 of 21 | NP_001401413.1 | |||
PET100 | NR_033242.2 | n.44G>C | non_coding_transcript_exon_variant | Exon 1 of 5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PET100 | ENST00000594797.6 | c.3G>C | p.Met1? | start_lost | Exon 1 of 4 | 1 | NM_001171155.2 | ENSP00000470539.1 | ||
ENSG00000268400 | ENST00000698368.1 | n.3G>C | non_coding_transcript_exon_variant | Exon 1 of 20 | ENSP00000513686.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000721 AC: 1AN: 138612Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 74336
GnomAD4 exome AF: 0.00000795 AC: 11AN: 1384244Hom.: 0 Cov.: 31 AF XY: 0.00000439 AC XY: 3AN XY: 683058
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change affects the initiator methionine of the PET100 mRNA. The next in-frame methionine is located at codon 10. This variant is present in population databases (no rsID available, gnomAD 0.004%). Disruption of the initiator codon has been observed in individuals with PET100-related conditions (PMID: 24462369, 32313153). It is commonly reported in individuals of Lebanese ancestry (PMID: 24462369, 31406627). ClinVar contains an entry for this variant (Variation ID: 125441). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PET100 function (PMID: 24462369). For these reasons, this variant has been classified as Pathogenic. -
Founder variant in Lebanese individuals with Leigh syndrome (Lim et al., 2014); Published functional studies demonstrated the protein did not assemble into the typical complex and was not imported into the mitochondria (Lim et al., 2014); This variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26506407, 24462369, 31406627, 32313153) -
Mitochondrial complex 4 deficiency, nuclear type 12 Pathogenic:2
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Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
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PET100-related disorder Pathogenic:1
The PET100 c.3G>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant was reported as a Lebanese founder variant in individuals with Leigh syndrome (see, for example, Lim et al. 2014. PubMed ID: 24462369; Riley et al. 2020. PubMed ID: 32313153). This variant is reported in 0.0040% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/). Taken together, we classify this variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at