rs797044511
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000260.4(MYO7A):c.1208A>G(p.Tyr403Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y403Y) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1208A>G | p.Tyr403Cys | missense_variant | 12/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1208A>G | p.Tyr403Cys | missense_variant | 12/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1208A>G | p.Tyr403Cys | missense_variant | 12/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1175A>G | p.Tyr392Cys | missense_variant | 13/50 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 16, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the MYO7A protein (p.Tyr403Cys). This variant is present in population databases (rs797044511, gnomAD 0.001%). This missense change has been observed in individual(s) with Usher syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 178667). 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 expected to disrupt MYO7A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Usher syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Dec 21, 2022 | The NM_000260.4:c.1208A>G variant in the MYO7A gene is a missense variant predicted to cause substitution of tyrosine to cysteine at amino acid 403 (p.Tyr403Cys).The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15398 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.941, evidence that correlates with impact to MYO7A function (PP3). This variant has been identified in 1 individual with clinical features consistent with Usher syndrome who harbored a pathogenic variant, c.6326C>T (p.Thr2109Ile), in trans. These variants segregated in a similarly affected sibling (SCV000205114.4) (PM3, PP1, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PM3, PM2_Supporting, PP1, PP3, PP4). (VCEP specifications version 2.0.0; December 21, 2022) - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 12, 2013 | The Tyr403Cys in MYO7A has been identified in two siblings with clinical feature s of Usher syndrome by our laboratory. Both siblings carried a second MYO7A vari ant on the other MYO7A allele. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest tha t the Tyr403Cys variant may impact the protein. In summary, this variant is like ly to be pathogenic, though additional studies are required to fully establish i ts clinical significance. - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 20, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at