rs56378658
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6
The NM_053025.4(MYLK):c.1133G>A(p.Arg378His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378G) has been classified as Likely benign.
Frequency
Consequence
NM_053025.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.1133G>A | p.Arg378His | missense_variant | 10/34 | ENST00000360304.8 | NP_444253.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.1133G>A | p.Arg378His | missense_variant | 10/34 | 5 | NM_053025.4 | ENSP00000353452 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000104 AC: 26AN: 250538Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135498
GnomAD4 exome AF: 0.000127 AC: 186AN: 1461792Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93AN XY: 727160
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2023 | Reported as a likely benign variant in one individual diagnosed with TAAD and did not segregate with disease in this individual's family (Poninska et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146836) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Aortic aneurysm, familial thoracic 7 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the MYLK protein (p.Arg378His). This variant is present in population databases (rs56378658, gnomAD 0.02%). This missense change has been observed in individual(s) with thoracic aortic aneurysms and dissections (PMID: 27146836). ClinVar contains an entry for this variant (Variation ID: 264282). 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. 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. - |
Likely benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Likely Benign, for Aortic aneurysm, familial thoracic 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:27146836). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS2-Supporting => BS2 downgraded in strength to supporting. - |
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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 01, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 24, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at