rs534384552
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_002474.3(MYH11):c.3281C>T(p.Ala1094Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,612,842 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. A1094T) has been classified as Uncertain significance.
Frequency
Consequence
NM_002474.3 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 |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.3281C>T | p.Ala1094Val | missense_variant | 25/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.3302C>T | p.Ala1101Val | missense_variant | 26/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.3302C>T | p.Ala1101Val | missense_variant | 26/42 | ||
MYH11 | NM_022844.3 | c.3281C>T | p.Ala1094Val | missense_variant | 25/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.3281C>T | p.Ala1094Val | missense_variant | 25/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.3302C>T | p.Ala1101Val | missense_variant | 26/43 | 1 | NM_001040113.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250688Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135600
GnomAD4 exome AF: 0.0000671 AC: 98AN: 1460548Hom.: 0 Cov.: 33 AF XY: 0.0000702 AC XY: 51AN XY: 726658
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74476
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 4 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 24, 2018 | The MYH11 c.3281C>T; p.Ala1094Val variant (rs534384552), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 201060). This variant is found on nine chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 1094 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Ala1094Val variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1101 of the MYH11 protein (p.Ala1101Val). This variant is present in population databases (rs534384552, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 201060). 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 MYH11 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2023 | This missense variant replaces alanine with valine at codon 1101 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282064 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 27, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2023 | Has been reported in an individual with familial TAAD, who also harbored variants in the SMAD4 and TGFBR1 genes (PMID: 30809044); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30809044) - |
Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at