rs16943604
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_002470.4(MYH3):c.699C>T(p.Asn233=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,613,636 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 29 hom., cov: 32)
Exomes 𝑓: 0.0059 ( 55 hom. )
Consequence
MYH3
NM_002470.4 synonymous
NM_002470.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.589
Genes affected
MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]
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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=-0.75).
BP6
?
Variant 17-10648593-G-A is Benign according to our data. Variant chr17-10648593-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.589 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1868/152236) while in subpopulation AFR AF= 0.0298 (1237/41538). AF 95% confidence interval is 0.0284. There are 29 homozygotes in gnomad4. There are 912 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1868 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.699C>T | p.Asn233= | synonymous_variant | 8/41 | ENST00000583535.6 | |
MYH3 | XM_011523870.4 | c.699C>T | p.Asn233= | synonymous_variant | 8/41 | ||
MYH3 | XM_011523871.3 | c.699C>T | p.Asn233= | synonymous_variant | 8/41 | ||
MYH3 | XM_047436127.1 | c.699C>T | p.Asn233= | synonymous_variant | 10/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.699C>T | p.Asn233= | synonymous_variant | 8/41 | 5 | NM_002470.4 | P1 | |
MYH3 | ENST00000579489.2 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0122 AC: 1853AN: 152118Hom.: 27 Cov.: 32
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GnomAD3 exomes AF: 0.00724 AC: 1821AN: 251490Hom.: 16 AF XY: 0.00741 AC XY: 1007AN XY: 135918
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GnomAD4 exome AF: 0.00587 AC: 8576AN: 1461400Hom.: 55 Cov.: 31 AF XY: 0.00594 AC XY: 4320AN XY: 727022
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GnomAD4 genome ? AF: 0.0123 AC: 1868AN: 152236Hom.: 29 Cov.: 32 AF XY: 0.0123 AC XY: 912AN XY: 74426
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Freeman-Sheldon syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Distal arthrogryposis type 2B1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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