rs767517186
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong
The NM_004369.4(COL6A3):c.8966-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000285 in 1,613,998 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 Pathogenic (★★).
Frequency
Consequence
NM_004369.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.8966-1G>C | splice_acceptor_variant, intron_variant | Intron 40 of 43 | ENST00000295550.9 | NP_004360.2 | ||
COL6A3 | NM_057167.4 | c.8348-1G>C | splice_acceptor_variant, intron_variant | Intron 39 of 42 | NP_476508.2 | |||
COL6A3 | NM_057166.5 | c.7145-1G>C | splice_acceptor_variant, intron_variant | Intron 37 of 40 | NP_476507.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250556Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135498
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461840Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19AN XY: 727224
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74340
ClinVar
Submissions by phenotype
Dystonia 27 Pathogenic:3
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not provided Pathogenic:2
Canonical splice site variant expected to result in aberrant splicing, and published functional studies demonstrate skipping of exon 41 (Zech et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 26004199, 26872670, 32037012, 34313030) -
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Bethlem myopathy 1A Pathogenic:1
This sequence change affects an acceptor splice site in intron 40 of the COL6A3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs767517186, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with autosomal recessive dystonia (PMID: 26004199). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant myopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 192263). Studies have shown that disruption of this splice site results in skipping of exon 41, but is expected to preserve the integrity of the reading-frame (PMID: 26004199). 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