rs397515984
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000256.3(MYBPC3):āc.2723A>Gā(p.Tyr908Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000726 in 1,377,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 30)
Exomes š: 0.0000073 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 missense
NM_000256.3 missense
Scores
11
8
1
Clinical Significance
Conservation
PhyloP100: 5.94
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.906
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2723A>G | p.Tyr908Cys | missense_variant | 26/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2723A>G | p.Tyr908Cys | missense_variant | 26/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2723A>G | p.Tyr908Cys | missense_variant | 25/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.*228A>G | 3_prime_UTR_variant, NMD_transcript_variant | 26/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
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30
GnomAD3 exomes AF: 0.00000697 AC: 1AN: 143516Hom.: 0 AF XY: 0.0000129 AC XY: 1AN XY: 77324
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GnomAD4 exome AF: 0.00000726 AC: 10AN: 1377856Hom.: 0 Cov.: 34 AF XY: 0.00000442 AC XY: 3AN XY: 678638
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GnomAD4 genome ? Cov.: 30
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 42655). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 908 of the MYBPC3 protein (p.Tyr908Cys). - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | This missense variant replaces tyrosine with cysteine at codon 908 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/143516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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 specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 04, 2013 | The Tyr908Cys variant in MYBPC3 has not been reported in the literature nor prev iously identified by our laboratory. The frequency of this variant in large Euro pean American and African American populations cannot be determined from the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), because coverag e at this position was insufficient or unavailable. Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sug gest that the Tyr908Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, additional stud ies are needed to fully assess the clinical significance of this variant. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 27, 2019 | This missense variant replaces tyrosine with cysteine at codon 908 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/143516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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 | AiLife Diagnostics, AiLife Diagnostics | Feb 18, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at