chr3-15456456-G-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_005677.4(COLQ):c.1074+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
COLQ
NM_005677.4 splice_donor_region, intron
NM_005677.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0003331
2
Clinical Significance
Conservation
PhyloP100: 1.53
Genes affected
COLQ (HGNC:2226): (collagen like tail subunit of asymmetric acetylcholinesterase) This gene encodes the subunit of a collagen-like molecule associated with acetylcholinesterase in skeletal muscle. Each molecule is composed of three identical subunits. Each subunit contains a proline-rich attachment domain (PRAD) that binds an acetylcholinesterase tetramer to anchor the catalytic subunit of the enzyme to the basal lamina. Mutations in this gene are associated with endplate acetylcholinesterase deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 3-15456456-G-A is Benign according to our data. Variant chr3-15456456-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536245.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000368 (56/152306) while in subpopulation AFR AF= 0.00132 (55/41568). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COLQ | NM_005677.4 | c.1074+4C>T | splice_donor_region_variant, intron_variant | ENST00000383788.10 | |||
COLQ | NM_080538.2 | c.1044+4C>T | splice_donor_region_variant, intron_variant | ||||
COLQ | NM_080539.4 | c.972+4C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COLQ | ENST00000383788.10 | c.1074+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_005677.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000119 AC: 30AN: 251318Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135838
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461700Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727160
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GnomAD4 genome AF: 0.000368 AC: 56AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 11, 2023 | - - |
Congenital myasthenic syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2022 | This sequence change falls in intron 14 of the COLQ gene. It does not directly change the encoded amino acid sequence of the COLQ protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201227079, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with COLQ-related conditions. ClinVar contains an entry for this variant (Variation ID: 536245). 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 is not likely to affect RNA splicing. 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. - |
COLQ-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 17, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at