rs371066956
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_004369.4(COL6A3):c.7375C>T(p.Arg2459Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,798 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 Uncertain significance (★★).
Frequency
Consequence
NM_004369.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.7375C>T | p.Arg2459Trp | missense_variant | Exon 36 of 44 | ENST00000295550.9 | NP_004360.2 | |
COL6A3 | NM_057167.4 | c.6757C>T | p.Arg2253Trp | missense_variant | Exon 35 of 43 | NP_476508.2 | ||
COL6A3 | NM_057166.5 | c.5554C>T | p.Arg1852Trp | missense_variant | Exon 33 of 41 | NP_476507.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251238Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135812
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461632Hom.: 0 Cov.: 34 AF XY: 0.0000481 AC XY: 35AN XY: 727068
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:3
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31069529, 30564623) -
Bethlem myopathy 1A Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2459 of the COL6A3 protein (p.Arg2459Trp). This variant is present in population databases (rs371066956, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of COL6A3-related conditions (PMID: 30564623, 31069529). ClinVar contains an entry for this variant (Variation ID: 284557). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL6A3 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at