rs374766654
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000260.4(MYO7A):c.4735G>A(p.Glu1579Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,532 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1579Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.4735G>A | p.Glu1579Lys | missense_variant | 35/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.4735G>A | p.Glu1579Lys | missense_variant | 35/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000443 AC: 11AN: 248256Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134782
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461312Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 726922
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74374
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2017 | The p.Glu1579Lys variant in MYO7A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 8/ 126284 of E uropean chromosomes and 5/ 34374 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374766654). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analyses do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Glu1579Lys variant is un certain. ACMG/AMP Criteria applied: None. - |
Usher syndrome type 1B Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1579 of the MYO7A protein (p.Glu1579Lys). This variant is present in population databases (rs374766654, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 504648). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at