rs762867111
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BS1_Supporting
The NM_001848.3(COL6A1):c.717+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000192 in 1,559,014 control chromosomes in the GnomAD database, including 1 homozygotes. 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_001848.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.717+4A>G | splice_region_variant, intron_variant | Intron 5 of 34 | ENST00000361866.8 | NP_001839.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152184Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 2AN: 166642Hom.: 0 AF XY: 0.0000113 AC XY: 1AN XY: 88440
GnomAD4 exome AF: 0.0000142 AC: 20AN: 1406830Hom.: 0 Cov.: 34 AF XY: 0.0000173 AC XY: 12AN XY: 694724
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152184Hom.: 1 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74348
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 24, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 09, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 19, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2020 | In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32065942, 30564623, 32403337) - |
Bethlem myopathy 1A Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 05, 2024 | This sequence change falls in intron 5 of the COL6A1 gene. It does not directly change the encoded amino acid sequence of the COL6A1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with clinical features of COL6A1-related conditions (PMID: 30564623, 32065942, 32403337, 32528171; internal data). ClinVar contains an entry for this variant (Variation ID: 284826). 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 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jun 23, 2016 | - - |
Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 27, 2024 | The COL6A1 c.717+4A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous state in an individual with limb-girdle muscular dystrophy 1A (Table S7, Nallamilli et al. 2018. PubMed ID: 30564623), in the heterozygous state with another COL6A1 variant in patients with COL6-related myopathies (Zanoteli et al. 2020. PubMed ID: 32065942; Internal Data, PreventionGenetics), and in the heterozygous state in individuals with COL6-related myopathies where a second variant was not reported (Gonzalez-Quereda et al. 2020. PubMed ID: 32403337; Supplementary Table 4, Töpf et al 2020. PubMed ID: 32528171). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction programs is not equivalent to functional evidence. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (Zhang. 1998. PubMed ID: 9536098; Buratti et al. 2007. PubMed ID: 17576681). This variant has conflicting classifications listed in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/284826/). This variant was reported in 0.0030% of alleles in individuals of European (non-Finnish) ancestry in gnomAD. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at