chr16-15726940-T-G
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1
The NM_002474.3(MYH11):c.3766A>C(p.Lys1256Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,613,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00020 ( 1 hom. )
Consequence
MYH11
NM_002474.3 missense
NM_002474.3 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 6.26
Genes affected
MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]
NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PP2
Missense variant where missense usually causes diseases, MYH11
BP4
Computational evidence support a benign effect (MetaRNN=0.138589).
BP6
Variant 16-15726940-T-G is Benign according to our data. Variant chr16-15726940-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263518.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000199 (291/1461146) while in subpopulation SAS AF= 0.000557 (48/86250). AF 95% confidence interval is 0.000431. There are 1 homozygotes in gnomad4_exome. There are 158 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.3766A>C | p.Lys1256Gln | missense_variant | 28/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.3787A>C | p.Lys1263Gln | missense_variant | 29/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.3787A>C | p.Lys1263Gln | missense_variant | 29/42 | ||
MYH11 | NM_022844.3 | c.3766A>C | p.Lys1256Gln | missense_variant | 28/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.3766A>C | p.Lys1256Gln | missense_variant | 28/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.3787A>C | p.Lys1263Gln | missense_variant | 29/43 | 1 | NM_001040113.2 | ||
ENST00000574212.1 | n.267T>G | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 151890Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000299 AC: 75AN: 250990Hom.: 1 AF XY: 0.000383 AC XY: 52AN XY: 135724
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GnomAD4 exome AF: 0.000199 AC: 291AN: 1461146Hom.: 1 Cov.: 30 AF XY: 0.000217 AC XY: 158AN XY: 726878
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152008Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 21, 2019 | The p.Lys1263Gln variant in MYH11 has been previously reported, but has been identified in 0.03% (39/129118) of European chromosomes in gnomAD, including 1 homozygous South Asian individual. It has been reported in ClinVar (ID 263518). Computational tools predict predict a impact to the protein, though this information is not predictive enough to determine pathogenicity. In summary, although the frequency of this variant suggests that it is benign, additional information is needed to determine its clinical significance. ACMG/AMP criteria applied: PP3 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2020 | Has been previously reported as a variant of uncertain significance in 2 individuals with TAAD in the published literature (Weerakkody et al., 2018).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 263518; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29543232) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 19, 2022 | The MYH11 c.3766A>C; p.Lys1256Gln variant (rs149241435), is reported in the literature in several individuals affected with thoracic aortic aneurysm and dissection (Chen 2021, Weerakkody 2018). However, this variant was reported in two probands with pathogenic variants in FBN1 and the MYH11 variant did not segregate within the two probands’ families, though specific clinical and inheritance information were not provided (Li 2021). This variant is reported in ClinVar (Variation ID: 263518) and is found in the South Asian population with an allele frequency of 0.0751% (23/30,616 alleles, including one homozygote) in the Genome Aggregation Database. The lysine at codon 1256 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.532). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Lys1256Gln variant is uncertain at this time. References: Chen ZR et al. Genetic variants in Chinese patients with sporadic Stanford type A aortic dissection. J Thorac Dis. 2021 Jul;13(7):4008-4022. PMID: 34422331. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232. - |
Aortic aneurysm, familial thoracic 4 Uncertain:2Benign:1
Uncertain significance, 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, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 27, 2021 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2023 | This missense variant replaces lysine with glutamine at codon 1263 of the MYH11 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with thoracic aortic aneurysm and dissection (PMID: 29543232, 34422331, 34498425). Two of these individuals also carried a pathogenic variant in the FBN1 gene that could explain the observed phenotype (PMID: 34498425). This variant has also been reported in one individual affected with ischemic stroke, but was also present in multiple healthy control individuals (PMID: 36973604). This variant has been identified in 81/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary 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 | Jul 12, 2016 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2013 | There is insufficient or conflicting evidence for classification of this alteration. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N
REVEL
Uncertain
Sift
Benign
T;T;.;T
Sift4G
Benign
T;T;T;T
Polyphen
0.98
.;.;.;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at