rs113542401
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_004369.4(COL6A3):c.5820C>T(p.Ser1940=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,614,210 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 2 hom. )
Consequence
COL6A3
NM_004369.4 synonymous
NM_004369.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.164
Genes affected
COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
Variant 2-237365716-G-A is Benign according to our data. Variant chr2-237365716-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237365716-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.164 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00251 (382/152334) while in subpopulation AFR AF= 0.00892 (371/41580). AF 95% confidence interval is 0.00817. There are 0 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 2 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.5820C>T | p.Ser1940= | synonymous_variant | 12/44 | ENST00000295550.9 | |
COL6A3 | NM_057167.4 | c.5202C>T | p.Ser1734= | synonymous_variant | 11/43 | ||
COL6A3 | NM_057166.5 | c.3999C>T | p.Ser1333= | synonymous_variant | 9/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A3 | ENST00000295550.9 | c.5820C>T | p.Ser1940= | synonymous_variant | 12/44 | 1 | NM_004369.4 | P1 | |
COL6A3 | ENST00000472056.5 | c.3999C>T | p.Ser1333= | synonymous_variant | 9/41 | 1 | |||
COL6A3 | ENST00000353578.9 | c.5202C>T | p.Ser1734= | synonymous_variant | 11/43 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00250 AC: 381AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000635 AC: 159AN: 250552Hom.: 0 AF XY: 0.000487 AC XY: 66AN XY: 135496
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GnomAD4 exome AF: 0.000276 AC: 404AN: 1461876Hom.: 2 Cov.: 32 AF XY: 0.000231 AC XY: 168AN XY: 727234
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GnomAD4 genome ? AF: 0.00251 AC: 382AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.00222 AC XY: 165AN XY: 74488
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 30, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | COL6A3: BP4, BP7 - |
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Bethlem myopathy 1A Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at