rs142765858
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_053025.4(MYLK):c.1957G>A(p.Glu653Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E653G) has been classified as Uncertain significance.
Frequency
Consequence
NM_053025.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.1957G>A | p.Glu653Lys | missense_variant | 15/34 | ENST00000360304.8 | |
LOC105369194 | XR_924417.4 | n.252-3476C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.1957G>A | p.Glu653Lys | missense_variant | 15/34 | 5 | NM_053025.4 | P4 | |
ENST00000685586.1 | n.612-3476C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251466Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135904
GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62AN XY: 727196
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
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 | Jul 29, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2017 | The p.E653K variant (also known as c.1957G>A), located in coding exon 12 of the MYLK gene, results from a G to A substitution at nucleotide position 1957. The glutamic acid at codon 653 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Aortic aneurysm, familial thoracic 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 653 of the MYLK protein (p.Glu653Lys). This variant is present in population databases (rs142765858, 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: 520001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 80%. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at