rs147187907
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6
The NM_053025.4(MYLK):c.5477C>T(p.Ala1826Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00063 ( 1 hom. )
Consequence
MYLK
NM_053025.4 missense
NM_053025.4 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 9.00
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 0 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYLK. . Gene score misZ 1.1317 (greater than the threshold 3.09). Trascript score misZ 3.1503 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, megacystis-microcolon-intestinal hypoperistalsis syndrome, aortic aneurysm, familial thoracic 7.
BP6
Variant 3-123618662-G-A is Benign according to our data. Variant chr3-123618662-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252775.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.5477C>T | p.Ala1826Val | missense_variant | 33/34 | ENST00000360304.8 | |
MYLK-AS1 | NR_038266.2 | n.290-10832G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.5477C>T | p.Ala1826Val | missense_variant | 33/34 | 5 | NM_053025.4 | P4 | |
MYLK-AS1 | ENST00000485162.5 | n.261-10832G>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000291 AC: 73AN: 251230Hom.: 0 AF XY: 0.000324 AC XY: 44AN XY: 135768
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GnomAD4 exome AF: 0.000629 AC: 919AN: 1461832Hom.: 1 Cov.: 31 AF XY: 0.000628 AC XY: 457AN XY: 727216
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GnomAD4 genome AF: 0.000223 AC: 34AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:8
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2023 | Identified in conjunction with a COL3A1 variant in an infant with a borderline aortic aneurysm; this proband's father, who had a TAA, was found to be heterozygous for both variants (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29961567, 29907982) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MYLK p.Ala1706Val variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs147187907), LOVD 3.0 (classified as a VUS) and in ClinVar (classified as a VUS by Invitae, GeneDx, Illumina, Ambry Genetics, EGL Genetic Diagnostics and the Division of Genomic Diagnostics at The Children's Hospital of Philadelphia). The variant was also identified in control databases in 78 of 282626 chromosomes at a frequency of 0.000276 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 59 of 128966 chromosomes (freq: 0.000458), South Asian in 10 of 30614 chromosomes (freq: 0.000327), African in 4 of 24968 chromosomes (freq: 0.00016), Other in 1 of 7212 chromosomes (freq: 0.000139), Latino in 3 of 35436 chromosomes (freq: 0.000085) and European (Finnish) in 1 of 25122 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Ala1706 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 22, 2020 | The MYLK c.5477C>T; p.Ala1826Val variant (rs147187907) is reported in the literature in an individual with a suspected heritable thoracic aortic disorder, but without clear association with disease (Overwater 2018). This variant is reported in ClinVar (Variation ID: 252775), and is found in the general population with an overall allele frequency of 0.028% (78/282626 alleles) in the Genome Aggregation Database. The alanine at codon 1826 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Ala1826Val variant is uncertain at this time. References: Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Dec 17, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 27, 2023 | The p.A1826V variant (also known as c.5477C>T), located in coding exon 30 of the MYLK gene, results from a C to T substitution at nucleotide position 5477. The alanine at codon 1826 is replaced by valine, an amino acid with similar properties. This variant co-occurred with a COL3A1 variant in a pediatric individual with borderline aortic root aneurysm and family history of aortic aneurysm (Overwater E. Hum Mutat. 2018 09;39(9):1173-1192). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Aortic aneurysm, familial thoracic 7 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2019 | Variant summary: MYLK c.5477C>T (p.Ala1826Val) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251230 control chromosomes, predominantly at a frequency of 0.00049 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 20-folds over the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5477C>T has been reported in the literature in individuals with suspected TAAD (Overwater_2018). This report does not provide an unequivocal conclusion about association of the variant with Aortopathy. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Kwartler_2018). Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;.;D;.;D;.
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;N;.;.;.;.;N
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
N;.;N;N;D;.;N;.;N
REVEL
Uncertain
Sift
Benign
T;.;T;T;T;.;T;.;T
Sift4G
Uncertain
T;T;T;D;D;D;T;D;D
Polyphen
D;D;D;D;.;.;D;.;D
Vest4
MVP
MPC
1.8
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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