rs143978652
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_002471.4(MYH6):c.3010G>T(p.Ala1004Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,160 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 2 hom. )
Consequence
MYH6
NM_002471.4 missense
NM_002471.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 2.47
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 -8 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.
BP4
Computational evidence support a benign effect (MetaRNN=0.02393347).
BP6
Variant 14-23393437-C-A is Benign according to our data. Variant chr14-23393437-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14151.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Likely_pathogenic=1, Benign=1, Uncertain_significance=4, Pathogenic=1}. Variant chr14-23393437-C-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 166 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3010G>T | p.Ala1004Ser | missense_variant | 23/39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3010G>T | p.Ala1004Ser | missense_variant | 23/39 | 5 | NM_002471.4 | ENSP00000386041 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00109 AC: 166AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000926 AC: 233AN: 251486Hom.: 0 AF XY: 0.000934 AC XY: 127AN XY: 135918
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GnomAD4 exome AF: 0.00110 AC: 1603AN: 1461892Hom.: 2 Cov.: 33 AF XY: 0.00105 AC XY: 763AN XY: 727246
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GnomAD4 genome AF: 0.00109 AC: 166AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87AN XY: 74452
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:5Benign:16
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:7
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | MYH6: BS1, BS2 - |
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 15, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 16, 2015 | p.Ala1004Ser in exon 23 of MYH6: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (31/11578) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs143978652). - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2019 | Variant summary: MYH6 c.3010G>T (p.Ala1004Ser) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 251486 control chromosomes, predominantly at a frequency of 0.0021 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 84 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 Latino origin. c.3010G>T has been reported in the literature in sequencing studies among individuals affected with Cardiomyopathy (Carniel_2005, Brion_2009, Brion_2012, Hershberger_2010, Posch_2011, Waldmuller_2010-unpublished poster, Merlo_2013). These data indicate that the variant may be associated with disease. At-least one co-occurrence with other pathogenic variant(s) has been reported (MYH7 c.1988G>A, p.R663H), providing supporting evidence for a benign role (Waldmuller_2010, unpublished poster abstract). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2017 | 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. - |
Hypertrophic cardiomyopathy 14 Uncertain:2Benign:1
Uncertain significance, flagged submission | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | research | Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute | Jul 24, 2024 | - - |
Wolff-Parkinson-White pattern Pathogenic:1
Likely pathogenic, flagged submission | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Jul 14, 2017 | This variant was identified in an individual with Wolff-Parkinson-White syndrome - |
Dilated cardiomyopathy 1EE Pathogenic:1
Pathogenic, flagged submission | literature only | OMIM | Jul 05, 2005 | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, flagged submission | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jun 30, 2016 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | research | Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics | - | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 22, 2019 | - - |
Primary dilated cardiomyopathy;C0042514:Ventricular tachycardia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Mar 04, 2019 | - - |
Primary dilated cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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