rs377745688
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000257.4(MYH7):c.3726+6C>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 0.000131 in 1,613,836 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 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
MYH7
NM_000257.4 splice_donor_region, intron
NM_000257.4 splice_donor_region, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.256
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 -3 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 14-23419839-G-A is Benign according to our data. Variant chr14-23419839-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42970.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4, Benign=1}. Variant chr14-23419839-G-A is described in Lovd as [Likely_benign]. Variant chr14-23419839-G-A is described in Lovd as [Benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.3726+6C>T | splice_donor_region_variant, intron_variant | ENST00000355349.4 | |||
MYH7 | NM_001407004.1 | c.3726+6C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.3726+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152130Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251314Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135810
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GnomAD4 exome AF: 0.000132 AC: 193AN: 1461706Hom.: 0 Cov.: 35 AF XY: 0.000122 AC XY: 89AN XY: 727160
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152130Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74296
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2022 | Reported in association with cardiomyopathy (Gruner et al., 2011; van Lint et al., 2019) and in one individual with HCM who harbored a co-occurring pathogenic variant in the MYBPC3 gene (Miller et al., 2013); In silico analysis supports a deleterious effect on splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 23054336, 30847666, 21511876) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 12, 2020 | - - |
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 02, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 11, 2019 | - - |
Myosin storage myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 25, 2020 | The c.3726+C>T variant in MYH7 is classified as likely benign because it has been identified in 0.018% (24/129010) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the 5' splice region; however, computational splice prediction tools do not predict an impact on splicing. Additionally, this variant has been identified in two individuals with HCM with additional variants in another cardiomyopathy gene that were sufficient to explain their observed phenotype (Miller 2013 PMID: 23054336; LMM internal data). ACMG/AMP Criteria applied: BS1, BP4. - |
MYH7-related skeletal myopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
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Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at