rs727504319
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000257.4(MYH7):c.5559+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000076 in 1,605,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 0 hom. )
Consequence
MYH7
NM_000257.4 splice_donor_region, intron
NM_000257.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.001065
2
Clinical Significance
Conservation
PhyloP100: -1.61
Genes affected
MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 14-23414991-G-A is Benign according to our data. Variant chr14-23414991-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177782.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5559+4C>T | splice_donor_region_variant, intron_variant | ENST00000355349.4 | |||
MYH7 | NM_001407004.1 | c.5559+4C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5559+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000448 AC: 11AN: 245684Hom.: 0 AF XY: 0.0000675 AC XY: 9AN XY: 133350
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GnomAD4 exome AF: 0.0000784 AC: 114AN: 1453840Hom.: 0 Cov.: 34 AF XY: 0.0000774 AC XY: 56AN XY: 723634
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74316
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2020 | Variant summary: MYH7 c.5559+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 4.7e-05 in 277054 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (4.7e-05 vs 0.0013), allowing no conclusion about variant significance. c.5559+4C>T has been reported in the literature in individuals affected with dilated cardiomyopathy and hypertrophic cardiomyopathy (Zimmerman_2010, Lopes_2015). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2013 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change falls in intron 37 of the MYH7 gene. It does not directly change the encoded amino acid sequence of the MYH7 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs727504319, gnomAD 0.007%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 177782). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2021 | The c.5559+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 35 in the MYH7 gene. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 09, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2019 | This variant is associated with the following publications: (PMID: 25351510, 20474083) - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at