rs397516766
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_002471.4(MYH6):c.3979-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 123,154 control chromosomes in the GnomAD database, including 30 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.013 ( 30 hom., cov: 26)
Exomes 𝑓: 0.0028 ( 19 hom. )
Failed GnomAD Quality Control
Consequence
MYH6
NM_002471.4 splice_region, splice_polypyrimidine_tract, intron
NM_002471.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.588
Genes affected
MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 14-23389061-GA-G is Benign according to our data. Variant chr14-23389061-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 44499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23389061-GA-G is described in Lovd as [Benign]. Variant chr14-23389061-GA-G is described in Lovd as [Likely_benign]. Variant chr14-23389061-GA-G is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3979-7del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3979-7del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0127 AC: 1562AN: 123084Hom.: 30 Cov.: 26
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GnomAD3 exomes AF: 0.00315 AC: 583AN: 184810Hom.: 6 AF XY: 0.00231 AC XY: 234AN XY: 101172
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00280 AC: 3832AN: 1366570Hom.: 19 Cov.: 27 AF XY: 0.00250 AC XY: 1697AN XY: 678616
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? AF: 0.0127 AC: 1567AN: 123154Hom.: 30 Cov.: 26 AF XY: 0.0124 AC XY: 753AN XY: 60486
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:7
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2016 | 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. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 01, 2015 | c.3979-7delT in intron 28 of MYH6: This variant is not expected to have clinical significance because it has been identified in 8.5% (304/3564) of African chrom osomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs397516766). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2020 | Variant summary: MYH6 c.3979-7delT 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 0.0032 in 184810 control chromosomes, predominantly at a frequency of 0.08 within the African or African-American subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3200 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3979-7delT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=4)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 16, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 23, 2018 | - - |
Hypertrophic cardiomyopathy 14 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 13, 2020 | - - |
Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Atrial septal defect Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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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