rs1297886521
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000260.4(MYO7A):c.1189G>A(p.Ala397Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000779 in 1,411,928 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A397D) has been classified as Likely pathogenic.
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.1189G>A | p.Ala397Thr | missense_variant | 11/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1189G>A | p.Ala397Thr | missense_variant | 11/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1189G>A | p.Ala397Thr | missense_variant | 11/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1156G>A | p.Ala386Thr | missense_variant | 12/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000779 AC: 11AN: 1411928Hom.: 0 Cov.: 31 AF XY: 0.00000717 AC XY: 5AN XY: 697826
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 397 of the MYO7A protein (p.Ala397Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Usher syndrome (PMID: 23591405, 28944237; Invitae). ClinVar contains an entry for this variant (Variation ID: 554214). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala397 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9382091, 18700726, 20497194). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 29, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at