rs759918870
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_001848.3(COL6A1):c.2431_2434+36del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A807A) has been classified as Likely benign.
Frequency
Consequence
NM_001848.3 splice_donor, splice_donor_5th_base, coding_sequence, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.2431_2434+36del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 33/35 | ENST00000361866.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A1 | ENST00000361866.8 | c.2431_2434+36del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 33/35 | 1 | NM_001848.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248576Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134614
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000821 AC: 12AN: 1460980Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 726784
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2017 | This sequence change removes the last 4 nucleotides of exon 33, and affects a donor splice site in intron 33 of the COL6A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A1 are known to be pathogenic (PMID: 19884007, 20976770). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. This variant has not been reported in the literature in individuals with COL6A1-related disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at