rs781988557
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000260.4(MYO7A):c.2863G>A(p.Gly955Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G955G) has been classified as Likely benign.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.2863G>A | p.Gly955Ser | missense_variant | 23/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.2863G>A | p.Gly955Ser | missense_variant | 23/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 247946Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134982
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461138Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6AN XY: 726808
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 955 of the MYO7A protein (p.Gly955Ser). This variant is present in population databases (rs781988557, gnomAD 0.03%). This missense change has been observed in individual(s) with Usher syndrome and autosomal recessive deafness (PMID: 9002678, 19074810, 21873662, 25211151, 29048421). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 177733). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO7A protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 27, 2021 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 14, 2014 | The Gly955Ser in MYO7A has been previously reported in two individuals with Ushe r syndrome (Levy 1997, Jacobson 2009). One individual had an affected sibling wh o was also heterozygous for this variant (Levy 1997), and the other individual w as also found to carry a second pathogenic variant in MYO7A (Jacobson 2009). Thi s variant was absent from large population studies. Conservation analyses sugges t this variant may not impact the protein, due to the presence of serine (Ser) i n several mammals at this position. However, splicing prediction tools suggest t he creation of a cryptic donor splice site; though, this information is not pred ictive enough to determine pathogenicity. In summary, although additional studie s are required to fully establish its clinical significance, this variant is lik ely pathogenic based on the previous reports and its presence in trans with a pa thogenic variant in this individual. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at