rs111033259
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong
The NM_000260.4(MYO7A):c.4544_4551delinsCA(p.Glu1515_Met1517delinsAla) variant causes a protein altering change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
MYO7A
NM_000260.4 protein_altering
NM_000260.4 protein_altering
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.67
Genes affected
MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000260.4.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 11-77198597-AGATCATG-CA is Pathogenic according to our data. Variant chr11-77198597-AGATCATG-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.4544_4551delinsCA | p.Glu1515_Met1517delinsAla | protein_altering_variant | 34/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.4544_4551delinsCA | p.Glu1515_Met1517delinsAla | protein_altering_variant | 34/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2023 | In-frame deletion of 3 amino acids and an insertion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16963483, 33576163, 27743452) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 08, 2022 | This variant, c.4544_4551delinsCA, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the MYO7A protein (p.Glu1515_Met1517delinsAla). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with clinical features of Usher syndrome (PMID: 16963483, 27743452; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.4543_4551delGAGATCATGinsGCA. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 07, 2011 | The Glu1515_Met1517delinsAla variant in MYO7A has been identified in three proba nds with Usher syndrome (personal communication, W. Kimberling and two in our la boratory). The variant replaces three amino acids with a single new amino acid a nd is therefore likely to impact protein function. In addition, two probands hav e a second pathogenic variant in MYO7A which further supports a causative role. And finally, one proband?s affected sibling was also found to harbor both the 64 39-2A>G variant and this MYO7A variant and parental testing showed the variants were in trans (on two separate copies of the gene). In summary, this data suppor ts the classification of this variant as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at