rs397516308
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000260.4(MYO7A):c.4293G>A(p.Trp1431Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,606,144 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000260.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.4293G>A | p.Trp1431Ter | stop_gained | 32/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.4293G>A | p.Trp1431Ter | stop_gained | 32/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000855 AC: 2AN: 233886Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126710
GnomAD4 exome AF: 0.0000172 AC: 25AN: 1453940Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11AN XY: 722456
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Usher syndrome type 1B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 20, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 21, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 43236). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 22135276). This variant is present in population databases (rs397516308, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Trp1431*) 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
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 01, 2015 | The p.Trp1431X variant in MYO7A has been reported in 1 individual with Usher syn drome (Le Quesne Stabej 2012). It has not bee identified in large population stu dies. This nonsense variant leads to a premature termination codon at position 1 431 which is predicted to lead to a truncated or absent protein. Loss of functio n of the MYO7A gene is an established disease mechanism in Usher syndrome. In s ummary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner. - |
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 19, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at