rs771515309
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PP3BS1_Supporting
The NM_002474.3(MYH11):c.3721C>T(p.Arg1241Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,611,784 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1241Q) 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.3721C>T | p.Arg1241Trp | missense_variant | 28/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.3742C>T | p.Arg1248Trp | missense_variant | 29/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.3742C>T | p.Arg1248Trp | missense_variant | 29/42 | ||
MYH11 | NM_022844.3 | c.3721C>T | p.Arg1241Trp | missense_variant | 28/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.3721C>T | p.Arg1241Trp | missense_variant | 28/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.3742C>T | p.Arg1248Trp | missense_variant | 29/43 | 1 | NM_001040113.2 | ||
ENST00000574212.1 | n.312G>A | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151878Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251180Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135794
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1459906Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726198
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151878Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2AN XY: 74146
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 07, 2023 | This missense variant replaces arginine with tryptophan at codon 1248 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 5/251180 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 | Oct 12, 2023 | The p.R1241W variant (also known as c.3721C>T), located in coding exon 27 of the MYH11 gene, results from a C to T substitution at nucleotide position 3721. The arginine at codon 1241 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 31, 2021 | - - |
Aortic aneurysm, familial thoracic 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1248 of the MYH11 protein (p.Arg1248Trp). This variant is present in population databases (rs771515309, gnomAD 0.01%). 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: 534151). 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. 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. - |
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 | Sep 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at