rs782539587
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000260.4(MYO7A):c.1258A>T(p.Lys420Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000958 in 1,461,390 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 stop_gained
NM_000260.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.04
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 11-77161030-A-T is Pathogenic according to our data. Variant chr11-77161030-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 504508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77161030-A-T is described in Lovd as [Pathogenic]. Variant chr11-77161030-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1258A>T | p.Lys420Ter | stop_gained | 12/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1258A>T | p.Lys420Ter | stop_gained | 12/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1258A>T | p.Lys420Ter | stop_gained | 12/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1225A>T | p.Lys409Ter | stop_gained | 13/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248542Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134846
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461390Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726918
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 16963483, 29692870, 31479088, 31456290, 31541171, 31964843) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 504508). This premature translational stop signal has been observed in individuals with MYO7A-related conditions (PMID: 23770805, 29692870, 31479088). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs782539587, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Lys420*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
Usher syndrome type 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Hearing loss, autosomal recessive Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
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 | Genetics and Molecular Pathology, SA Pathology | Feb 09, 2023 | The MYO7A c.1258A>T variant is classified as a PATHOGENIC variant (PVS1, PM3_Strong) This variant is a single nucleotide change in exon 12/49 of the MYO7A gene, which is predicted to result in premature termination of the protein product at codon 420, causing loss of normal protein function (PVS1). The variant has been reported homozygous or compound heterozygous with another pathogenic MYO7A variant in multiple unrelated individuals affected with hearing loss or Usher syndrome (PMID: 22135276, 23770805, 27460420, 29692870, 31479088) (PM3_Strong). The variant has been reported in dbSNP (rs782539587) but is rare in population databases (gmomAD v2: 4/124267, 0 homozygotes). The variant has been reported in ClinVar (Variation ID: #504508) and HGMD (Accession no.: CM071018) as pathogenic/disease causing. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 11, 2017 | The p.Lys420X variant in MYO7A has been identified in the homozygous or compound heterozygous state in 6 individuals with clinical features of Usher syndrome (B onnet 2016, Le Quesne Stabej 2012, Shahzad 2013). In one study, this variant was identified in the homozygous state in 4 separate families of Pakistani descent with histories of consanguinity and segregated in over 10 affected family member s (Shahzad 2013). It has also been identified in 4/235612 chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7825 39587); however, this frequency is low enough to be consistent with a carrier fr equency for recessive Usher syndrome. The p.Lys420X nonsense variant leads to a premature termination codon at position 420, which is predicted to lead to a tru ncated or absent protein. Loss of MYO7A gene function is an established disease mechanism for autosomal recessive Usher syndrome. In summary, this variant meet s criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, homozygosity and compound zygosit y in affected individuals, segregation evidence, and low frequency in the genera l population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
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