chr3-123701433-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_053025.4(MYLK):c.2462+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000289 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
MYLK
NM_053025.4 splice_donor_5th_base, intron
NM_053025.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 5.84
Genes affected
MYLK (HGNC:7590): (myosin light chain kinase) This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.2462+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000360304.8 | |||
LOC105369194 | XR_924417.4 | n.108-2433C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.2462+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | NM_053025.4 | P4 | |||
ENST00000685586.1 | n.126C>T | non_coding_transcript_exon_variant | 1/3 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251436Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135902
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GnomAD4 exome AF: 0.000312 AC: 456AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 225AN XY: 727194
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 7 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change falls in intron 17 of the MYLK gene. It does not directly change the encoded amino acid sequence of the MYLK protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374003770, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 504425). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 25, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2021 | The c.2462+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 14 in the MYLK gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 26, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Intronic +5 splice site variant, both splice predictors and evolutionary conservation support a deleterious effect; however, in the absence of functional evidence, the actual effect of this sequence change is unknown; Not located in the smooth muscle isoform, where the majority of loss-of-function variants associated with autosomal dominant TAAD and autosomal recessive MMIHS have been reported to date (Wang et al., 2010; Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 2290495; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533) - |
Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 17, 2022 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at