rs528507616
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_053025.4(MYLK):c.2663G>A(p.Arg888His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,198 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R888C) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.2663G>A | p.Arg888His | missense_variant | 18/34 | ENST00000360304.8 | |
LOC105369194 | XR_924417.4 | n.108-3061C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.2663G>A | p.Arg888His | missense_variant | 18/34 | 5 | NM_053025.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251344Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135878
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461874Hom.: 0 Cov.: 40 AF XY: 0.0000110 AC XY: 8AN XY: 727242
GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152324Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74480
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 423801). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. This variant is present in population databases (rs528507616, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 888 of the MYLK protein (p.Arg888His). - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 28, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2018 | The R888H variant has not been publishedas pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R888Hsubstitution occurs at a position where only amino acids with similar properties to arginine (R) are tolerated acrossspecies. However, R888H is a conservative amino acid substitution, which is not likely to impact secondary proteinstructure as these residues share similar properties. Finally, in silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at