chr3-123733085-G-A
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_053025.4(MYLK):c.1327C>T(p.Pro443Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0171 in 1,613,872 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P443T) has been classified as Likely benign.
Frequency
Consequence
NM_053025.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.1327C>T | p.Pro443Ser | missense_variant | 11/34 | ENST00000360304.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.1327C>T | p.Pro443Ser | missense_variant | 11/34 | 5 | NM_053025.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0123 AC: 1865AN: 152138Hom.: 16 Cov.: 32
GnomAD3 exomes AF: 0.0141 AC: 3514AN: 249246Hom.: 32 AF XY: 0.0147 AC XY: 1989AN XY: 134866
GnomAD4 exome AF: 0.0176 AC: 25769AN: 1461616Hom.: 255 Cov.: 35 AF XY: 0.0175 AC XY: 12720AN XY: 727074
GnomAD4 genome AF: 0.0122 AC: 1863AN: 152256Hom.: 15 Cov.: 32 AF XY: 0.0115 AC XY: 856AN XY: 74426
ClinVar
Submissions by phenotype
not specified Benign:8
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2013 | Pro443Ser in exon 11 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 2.0% (176/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35156360). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 05, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2019 | Variant summary: MYLK c.1327C>T (p.Pro443Ser) results in a non-conservative amino acid change located in one of the immunoglobulin subtype 2 domains (IPR003598) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.014 in 280644 control chromosomes (predominantly reported within the Ashkenazi Jewish and Non-Finnish European subpopulations) in the gnomAD database, including 35 homozygotes. The observed variant frequency within the gnomAD database is approximately 500 fold of 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. Though the variant, c.1327C>T, has been reported to be found in a cohort of patients with familial abdominal aortic aneurysm, however, the variant was noted to be a part of complex genotypes, and it did not segregate with the disease in at least one family (van de Luijtgaarden_2015). To our knowledge no experimental evidence demonstrating its impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cites the variant five times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Aortic aneurysm, familial thoracic 7 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2015 | This alteration is classified as 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. - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 18, 2022 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | MYLK: BP4, BS1, BS2 - |
Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 02, 2022 | MYLK NM_053025.3 exon 11 p.Pro443Ser (c.1327C>T): This variant has been reported in the literature in one individual with an abdominal aortic aneurysm (van de Luijtgaarden 2015 PMID:26017485). However, this variant is also present in 1.8% (1212/64560) of European alleles in the Genome Aggregation Database, including 11 homozygotes (https://gnomad.broadinstitute.org/variant/3-123733085-G-A?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:226754). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at