rs199755371
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1
The NM_002474.3(MYH11):c.633+1942T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000639 in 1,613,724 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00062 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00064 ( 1 hom. )
Consequence
MYH11
NM_002474.3 intron
NM_002474.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.363
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
Variant 16-15784688-A-G is Benign according to our data. Variant chr16-15784688-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15784688-A-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000624 (95/152212) while in subpopulation AMR AF= 0.00203 (31/15282). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_001040113.2 | c.654+10T>C | intron_variant | ENST00000452625.7 | |||
MYH11 | NM_002474.3 | c.633+1942T>C | intron_variant | ENST00000300036.6 | |||
MYH11 | NM_001040114.2 | c.654+10T>C | intron_variant | ||||
MYH11 | NM_022844.3 | c.633+1942T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.633+1942T>C | intron_variant | 1 | NM_002474.3 | P3 | |||
MYH11 | ENST00000452625.7 | c.654+10T>C | intron_variant | 1 | NM_001040113.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000625 AC: 95AN: 152094Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.000414 AC: 103AN: 249030Hom.: 1 AF XY: 0.000437 AC XY: 59AN XY: 135106
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GnomAD4 exome AF: 0.000640 AC: 936AN: 1461512Hom.: 1 Cov.: 30 AF XY: 0.000608 AC XY: 442AN XY: 727054
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GnomAD4 genome ? AF: 0.000624 AC: 95AN: 152212Hom.: 0 Cov.: 30 AF XY: 0.000578 AC XY: 43AN XY: 74422
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2018 | Variant summary: MYH11 c.654+10T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0004 in 276970 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 321-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.654+10T>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2014 | 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:3
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Dec 15, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Mar 31, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 27, 2018 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 01, 2022 | - - |
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