chr16-15748152-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS1
The NM_002474.3(MYH11):c.2075C>T(p.Ala692Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,613,786 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A692A) has been classified as Likely benign.
Frequency
Consequence
NM_002474.3 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 | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.2075C>T | p.Ala692Val | missense_variant | 17/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.2096C>T | p.Ala699Val | missense_variant | 18/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.2096C>T | p.Ala699Val | missense_variant | 18/42 | ||
MYH11 | NM_022844.3 | c.2075C>T | p.Ala692Val | missense_variant | 17/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.2075C>T | p.Ala692Val | missense_variant | 17/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.2096C>T | p.Ala699Val | missense_variant | 18/43 | 1 | NM_001040113.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000263 AC: 40AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000255 AC: 64AN: 250856Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135682
GnomAD4 exome AF: 0.000624 AC: 912AN: 1461584Hom.: 1 Cov.: 34 AF XY: 0.000637 AC XY: 463AN XY: 727088
GnomAD4 genome ? AF: 0.000263 AC: 40AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 17, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2023 | Identified in a patient with severe arterial tortuosity and coarctation of the aorta, and in the asymptomatic mother (Loup et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23696586) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2023 | The MYH11 c.2075C>T; p.Ala692Val variant (rs148893135), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.002 % (69/ 282,246 alleles) in the Genome Aggregation Database. The alanine at codon 692 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Ala692Val variant is uncertain at this time. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 14, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2023 | The p.A692V variant (also known as c.2075C>T), located in coding exon 16 of the MYH11 gene, results from a C to T substitution at nucleotide position 2075. The alanine at codon 692 is replaced by valine, an amino acid with similar properties. This alteration was reported in an infant with arterial tortuosity and the unaffected mother (Loup O et al. Circ Cardiovasc Imaging, 2013 May;6:487-90). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2023 | This missense variant replaces alanine with valine at codon 699 of the MYH11 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an asymptomatic infant with severe arterial tortuosity and coarctation and in her unaffected mother (variant cited as MYH11 c.2075C>T, p.Ala692Val, using a different transcript, PMID: 23696586). This variant has been identified in 69/282246 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. - |
Aortic aneurysm, familial thoracic 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 699 of the MYH11 protein (p.Ala699Val). This variant is present in population databases (rs148893135, gnomAD 0.05%). 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: 201054). 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 with a negative predictive value of 95%. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2023 | Variant summary: MYH11 c.2096C>T (p.Ala699Val) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 250856 control chromosomes, predominantly at a frequency of 0.00049 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 392 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2096C>T has been reported in the literature in an individual with a clinical phenotype that is not compatible with thoracic aortic aneurysm; her unaffected mother also carried the variant (Loup_2013). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at