rs397516326
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000260.4(MYO7A):c.6025del(p.Ala2009ProfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,573,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000052 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 frameshift
NM_000260.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.93
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
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-77208775-TG-T is Pathogenic according to our data. Variant chr11-77208775-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 43313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77208775-TG-T is described in Lovd as [Pathogenic]. Variant chr11-77208775-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr11-77208775-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.6025del | p.Ala2009ProfsTer32 | frameshift_variant | 44/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.6025del | p.Ala2009ProfsTer32 | frameshift_variant | 44/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000534 AC: 1AN: 187354Hom.: 0 AF XY: 0.0000100 AC XY: 1AN XY: 99892
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GnomAD4 exome AF: 0.0000521 AC: 74AN: 1421616Hom.: 0 Cov.: 32 AF XY: 0.0000370 AC XY: 26AN XY: 703338
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 07, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Jan 30, 2015 | - - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 07, 2017 | - - |
Usher syndrome type 1B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Ala2009Profs*32) 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). This variant is present in population databases (rs752136791, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 10930322, 25404053). This variant is also known as Met2018 (1-bp del G). ClinVar contains an entry for this variant (Variation ID: 43313). For these reasons, this variant has been classified as Pathogenic. - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 09, 2021 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 17, 2016 | The p.Ala2009fs variant in MYO7A has been reported in at least 10 unrelated indi viduals with Usher syndrome including 4 homozygotes and 3 compound heterozygotes , segregated with disease in one family, and was absent from over 400 race-match ed control chromosomes or large population studies (Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Maubaret 2005, Najera 2002, Roux 2006, LMM data). This variant is predicted to cause a frameshift, which alters the protein's amino aci d sequence beginning at codon 2009 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathoge nic for Usher syndrome in an autosomal recessive manner. ACMG/AMP Criteria appli ed: PVS1, PM2, PM3_Very Strong, PP4. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 08, 2019 | - - |
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