rs121908461
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PP5_Very_Strong
The NM_006790.3(MYOT):c.116C>T(p.Ser39Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Genomes: not found (cov: 32)
Consequence
MYOT
NM_006790.3 missense
NM_006790.3 missense
Scores
4
9
4
Clinical Significance
Conservation
PhyloP100: 5.37
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 Pathogenic. Variant got 14 ACMG points.
PS1
Transcript NM_006790.3 (MYOT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
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
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-137870767-C-T is Pathogenic according to our data. Variant chr5-137870767-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137870767-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYOT | NM_006790.3 | c.116C>T | p.Ser39Phe | 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.116C>T | p.Ser39Phe | missense_variant | 2/10 | 1 | NM_006790.3 | ENSP00000239926.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Myofibrillar myopathy 3 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 11, 2022 | For these reasons, this variant has been classified as Pathogenic. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 39 of the MYOT protein (p.Ser39Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MYOT-related conditions (PMID: 16380616, 22106715). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5839). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 14, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 27, 2005 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 05, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Loss of phosphorylation at S39 (P = 0.0243);
MVP
MPC
ClinPred
D
GERP RS
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