rs387906882
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3PP5BS2
The NM_006790.3(MYOT):c.17G>A(p.Arg6His) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,856 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
MYOT
NM_006790.3 missense
NM_006790.3 missense
Scores
8
6
3
Clinical Significance
Conservation
PhyloP100: 5.21
Genes affected
MYOT (HGNC:12399): (myotilin) This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM1
In a region_of_interest Disordered (size 45) in uniprot entity MYOTI_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006790.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.803
PP5
Variant 5-137870668-G-A is Pathogenic according to our data. Variant chr5-137870668-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30407.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr5-137870668-G-A is described in Lovd as [Pathogenic].
BS2
High AC in GnomAdExome4 at 45 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYOT | NM_006790.3 | c.17G>A | p.Arg6His | missense_variant | 2/10 | ENST00000239926.9 | NP_006781.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYOT | ENST00000239926.9 | c.17G>A | p.Arg6His | missense_variant | 2/10 | 1 | NM_006790.3 | ENSP00000239926.4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152072Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250430Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135442
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727198
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74282
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Myofibrillar myopathy 3 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 22, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 30407). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 21336781). This variant is present in population databases (rs387906882, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 6 of the MYOT protein (p.Arg6His). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 03, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2025 | Reported previously in an individual with late-onset progressive limb-girdle muscle weakness and respiratory insufficiency (PMID: 21336781); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24928145, 20301582, 34426522, 21336781, 22349301) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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