11-77155908-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000260.4(MYO7A):c.287C>T(p.Thr96Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,596,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T96T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000260.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.287C>T | p.Thr96Met | missense_variant, splice_region_variant | 5/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.287C>T | p.Thr96Met | missense_variant, splice_region_variant | 5/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.287C>T | p.Thr96Met | missense_variant, splice_region_variant | 5/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.254C>T | p.Thr85Met | missense_variant, splice_region_variant | 6/50 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000130 AC: 3AN: 230894Hom.: 0 AF XY: 0.0000240 AC XY: 3AN XY: 124768
GnomAD4 exome AF: 0.00000554 AC: 8AN: 1444528Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4AN XY: 716076
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74386
ClinVar
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 05, 2014 | The p.Thr96Met variant in MYO7A has been identified by our laboratory in one ind ividual with sensorineural hearing loss and retinitis pigmentosa and segregated with disease in one affected relative. Both individuals carried this variant in trans with a second pathogenic variant in MYO7A. Computational prediction tools and conservation analyses suggest that the p.Thr98Met variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. However, the presence of this variant in combination with a reported pathogen ic variant and in an individual with hearing loss and retinitis pigmentosa, incr eases the likelihood that the p.Thr96Met variant is pathogenic. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 96 of the MYO7A protein (p.Thr96Met). This variant is present in population databases (rs781811444, gnomAD 0.01%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 27344577). ClinVar contains an entry for this variant (Variation ID: 179974). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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