rs111033239
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000260.4(MYO7A):c.3532delC(p.Gln1178fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 frameshift
NM_000260.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.56
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-77189371-GC-G is Pathogenic according to our data. Variant chr11-77189371-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.3532delC | p.Gln1178fs | frameshift_variant | 28/49 | ENST00000409709.9 | NP_000251.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.3532delC | p.Gln1178fs | frameshift_variant | 28/49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.3532delC | p.Gln1178fs | frameshift_variant | 28/49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.3499delC | p.Gln1167fs | frameshift_variant | 29/50 | 1 | ENSP00000386635.2 | |||
MYO7A | ENST00000458169.2 | c.1075delC | p.Gln359fs | frameshift_variant | 8/29 | 1 | ENSP00000417017.2 | |||
MYO7A | ENST00000670577.1 | n.1372delC | non_coding_transcript_exon_variant | 11/32 | ENSP00000499323.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461412Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726980
GnomAD4 exome
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31
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1
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43209). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1178Serfs*2) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2008 | - - |
Computational scores
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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