rs794729642
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_002474.3(MYH11):c.5213T>C(p.Ile1738Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,598,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1738I) has been classified as Likely benign.
Frequency
Consequence
NM_002474.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.5213T>C | p.Ile1738Thr | missense_variant | 37/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.5234T>C | p.Ile1745Thr | missense_variant | 38/43 | ENST00000452625.7 | |
NDE1 | NM_017668.3 | c.948-5794A>G | intron_variant | ENST00000396354.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.5213T>C | p.Ile1738Thr | missense_variant | 37/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.5234T>C | p.Ile1745Thr | missense_variant | 38/43 | 1 | NM_001040113.2 | ||
NDE1 | ENST00000396354.6 | c.948-5794A>G | intron_variant | 1 | NM_017668.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1446404Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 719112
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | This missense variant replaces isoleucine with threonine at codon 1745 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 1/260456 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 | Color Diagnostics, LLC DBA Color Health | May 17, 2023 | This missense variant replaces isoleucine with threonine at codon 1745 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 1/260456 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 | Ambry Genetics | Feb 22, 2024 | The p.I1738T variant (also known as c.5213T>C), located in coding exon 36 of the MYH11 gene, results from a T to C substitution at nucleotide position 5213. The isoleucine at codon 1738 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Aortic aneurysm, familial thoracic 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 02, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1745 of the MYH11 protein (p.Ile1745Thr). This variant is present in population databases (rs794729642, gnomAD 0.0009%). 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: 203373). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Mar 24, 2015 | This variant (c.5234T>C) is classified as a variant of uncertain significance (VUS) because it has not previously been reported in literature and does not occur in a large database of control samples (ExAC 0.3). Computational evidence is suggestive of a pathogenic variant. It is located in highly conserved nucleotide and amino acid positions and occurs in the myosin tail functional domain according to InterPro. Furthermore, the amino acid substitution involves a change from isoleucine to threonine, which is not a conservative alteration. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | MYH11: PM2, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at