chr18-3079241-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_003803.4(MYOM1):āc.4586A>Gā(p.Tyr1529Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,834 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: š 0.000013 ( 0 hom., cov: 31)
Exomes š: 0.0000034 ( 0 hom. )
Consequence
MYOM1
NM_003803.4 missense
NM_003803.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.65
Genes affected
MYOM1 (HGNC:7613): (myomesin 1) The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD (myomesin 1) and 165 kD (myomesin 2). This protein, myomesin 1, like myomesin 2, titin, and other myofibrillar proteins contains structural modules with strong homology to either fibronectin type III (motif I) or immunoglobulin C2 (motif II) domains. Myomesin 1 and myomesin 2 each have a unique N-terminal region followed by 12 modules of motif I or motif II, in the arrangement II-II-I-I-I-I-I-II-II-II-II-II. The two proteins share 50% sequence identity in this repeat-containing region. The head structure formed by these 2 proteins on one end of the titin string extends into the center of the M band. The integrating structure of the sarcomere arises from muscle-specific members of the superfamily of immunoglobulin-like proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.94
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYOM1 | NM_003803.4 | c.4586A>G | p.Tyr1529Cys | missense_variant | 34/38 | ENST00000356443.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYOM1 | ENST00000356443.9 | c.4586A>G | p.Tyr1529Cys | missense_variant | 34/38 | 1 | NM_003803.4 | P2 | |
MYOM1 | ENST00000261606.11 | c.4298A>G | p.Tyr1433Cys | missense_variant | 33/37 | 1 | A2 | ||
MYOM1 | ENST00000581075.1 | c.*232A>G | 3_prime_UTR_variant, NMD_transcript_variant | 7/8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461634Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727106
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 18, 2016 | The p.Tyr1529Cys variant in MYOM1 has not been previously reported in individual s with cardiomyopathy or in large population studies. Computational prediction t ools and conservation analysis suggest that the p.Tyr1529Cys variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Tyr1529Cys variant is u ncertain. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1529 of the MYOM1 protein (p.Tyr1529Cys). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYOM1 protein function. ClinVar contains an entry for this variant (Variation ID: 229027). This variant has not been reported in the literature in individuals affected with MYOM1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
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
Pathogenic
D;.;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of methylation at K1528 (P = 0.0137);.;.;
MVP
MPC
ClinPred
D
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