chr3-193692066-AAGTT-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_130837.3(OPA1):c.2990_2993del(p.Val997GlufsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,360,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Consequence
OPA1
NM_130837.3 frameshift
NM_130837.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.30
Genes affected
OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-193692066-AAGTT-A is Pathogenic according to our data. Variant chr3-193692066-AAGTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193692066-AAGTT-A is described in Lovd as [Pathogenic]. Variant chr3-193692066-AAGTT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OPA1 | NM_130837.3 | c.2990_2993del | p.Val997GlufsTer25 | frameshift_variant | 30/31 | ENST00000361510.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OPA1 | ENST00000361510.8 | c.2990_2993del | p.Val997GlufsTer25 | frameshift_variant | 30/31 | 5 | NM_130837.3 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 0.00000147 AC: 2AN: 1360024Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 676598
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5083). This variant is also known as c.2823delAGTT or c.2823del4. This frameshift has been observed in individual(s) with dominant optic atrophy (PMID: 11017079). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the OPA1 gene (p.Val942Glufs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the OPA1 protein and extend the protein by 5 additional amino acid residues. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | Frameshift variant predicted to result in protein truncation, as the last 19 amino acids are replaced with 24 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17415700, 11017079, 28848318, 34242285, 25794858) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 07, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 20, 2016 | - - |
Autosomal dominant optic atrophy classic form Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2000 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at