rs1250409781
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_025136.4(OPA3):c.142+5G>C variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000274 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_025136.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OPA3 | NM_025136.4 | c.142+5G>C | splice_donor_5th_base_variant, intron_variant | ENST00000263275.5 | |||
OPA3 | NM_001017989.3 | c.142+5G>C | splice_donor_5th_base_variant, intron_variant | ||||
OPA3 | XM_006723403.5 | c.-158+5G>C | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OPA3 | ENST00000263275.5 | c.142+5G>C | splice_donor_5th_base_variant, intron_variant | 1 | NM_025136.4 | P1 | |||
OPA3 | ENST00000323060.4 | c.142+5G>C | splice_donor_5th_base_variant, intron_variant | 1 | |||||
OPA3 | ENST00000544371.1 | c.-18+17477G>C | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251248Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727238
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
3-Methylglutaconic aciduria type 3 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Nov 12, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The OPA3 c.142+5G>C variant has been reported in compond heterozygous state in individuals affected with 3-methylglutaconic aciduria, type III (Christina et. al., 2014). The c.142+5G>C variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD database. This variant has been reported to the ClinVar database as Likely pathogenic and Uncertain Significance. The variant does not affect an invariant splice nucleotide and in the absence of functional studies, this variant has been classified as Variant of Uncertain Significance (VUS). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
3-Methylglutaconic aciduria type 3;C1833809:Optic atrophy 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2023 | This sequence change falls in intron 1 of the OPA3 gene. It does not directly change the encoded amino acid sequence of the OPA3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with OPA3-related 3-methylglutaconic aciduria (PMID: 24749080). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553096). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at