rs141031021
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_002474.3(MYH11):c.4659C>T(p.Asp1553=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,614,072 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 2 hom. )
Consequence
MYH11
NM_002474.3 synonymous
NM_002474.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.569
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 16-15720971-G-A is Benign according to our data. Variant chr16-15720971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 386837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15720971-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.569 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000139 (203/1461878) while in subpopulation AFR AF= 0.00152 (51/33480). AF 95% confidence interval is 0.00119. There are 2 homozygotes in gnomad4_exome. There are 128 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.4659C>T | p.Asp1553= | synonymous_variant | 33/41 | ENST00000300036.6 | NP_002465.1 | |
MYH11 | NM_001040113.2 | c.4680C>T | p.Asp1560= | synonymous_variant | 34/43 | ENST00000452625.7 | NP_001035202.1 | |
NDE1 | NM_017668.3 | c.948-3220G>A | intron_variant | ENST00000396354.6 | NP_060138.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.4659C>T | p.Asp1553= | synonymous_variant | 33/41 | 1 | NM_002474.3 | ENSP00000300036 | P3 | |
MYH11 | ENST00000452625.7 | c.4680C>T | p.Asp1560= | synonymous_variant | 34/43 | 1 | NM_001040113.2 | ENSP00000407821 | ||
NDE1 | ENST00000396354.6 | c.948-3220G>A | intron_variant | 1 | NM_017668.3 | ENSP00000379642 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 251468Hom.: 1 AF XY: 0.000250 AC XY: 34AN XY: 135910
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GnomAD4 exome AF: 0.000139 AC: 203AN: 1461878Hom.: 2 Cov.: 32 AF XY: 0.000176 AC XY: 128AN XY: 727244
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GnomAD4 genome AF: 0.000145 AC: 22AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74406
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ClinVar
Significance: Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 16, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 14, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Aortic aneurysm, familial thoracic 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 05, 2023 | - - |
MYH11-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 11, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | MYH11: BP4, BP7 - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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