11-77162150-T-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000260.4(MYO7A):āc.1374T>Gā(p.Asn458Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,568 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N458I) has been classified as Pathogenic.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1374T>G | p.Asn458Lys | missense_variant | 13/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1374T>G | p.Asn458Lys | missense_variant | 13/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1374T>G | p.Asn458Lys | missense_variant | 13/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1341T>G | p.Asn447Lys | missense_variant | 14/50 | 1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000427 AC: 1AN: 234348Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126290
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1451568Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 720596
GnomAD4 genome Cov.: 33
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 | May 10, 2016 | The p.Asn458Lys variant in MYO7A has not been previously reported in individuals with hearing loss or Usher syndrome; however, a different variant at this amino acid position (p.Asn458Ile) has been previously reported in an individual with autosomal dominant hearing loss that segregated in 8 affected family members (Lu ijendijk 2004). Data from large population studies is insufficient to assess th e frequency of the p.Asn458Lys or the p.Asn458Ile variant. Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Asn458 Lys variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 458 of the MYO7A protein (p.Asn458Lys). 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. 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. ClinVar contains an entry for this variant (Variation ID: 504950). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at