rs373043783
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000257.4(MYH7):c.1407+4A>C 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 0.0000266 in 1,614,062 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
MYH7
NM_000257.4 splice_donor_region, intron
NM_000257.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9937
2
Clinical Significance
Conservation
PhyloP100: 2.58
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 Uncertain_significance. Variant got 1 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1407+4A>C | splice_donor_region_variant, intron_variant | ENST00000355349.4 | |||
MYH7 | NM_001407004.1 | c.1407+4A>C | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1407+4A>C | splice_donor_region_variant, intron_variant | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251452Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135910
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GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 727246
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 09, 2019 | This variant is located in the splice donor region in intron 14 of the MYH7 gene. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 20/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical significance of loss-of-function MYH7 truncations and splice variants in autosomal dominant cardiomyopathy is not clearly established. Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2014 | c.1407+4 A>C: IVS14+4 A>C in intron 14 of the MYH7 gene (NM_000257.2). A variant of unknown significance has been identified in the MYH7 gene. The c.1407+4 A>C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. In silico splice algorithms predict c.1407+4 A>C may negatively impact the natural splice donor site in intron 14. Splice site mutations in the MYH7 gene have been reported in association with cardiomyopathy, however, the vast majority of mutations in MYH7 are missense changes. Furthermore, various studies have conflicting hypotheses regarding MYH7 haploinsufficiency leading to cardiomyopathy (Nishi H et al., 1995; Waldmuller S et al., 2011). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change falls in intron 14 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 (rs373043783, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181346). 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at