chr17-18155423-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_016239.4(MYO15A):c.8450G>A(p.Arg2817His) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R2817C) has been classified as Uncertain significance.
Frequency
Consequence
NM_016239.4 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 |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.8450G>A | p.Arg2817His | missense_variant | 47/66 | ENST00000647165.2 | |
MYO15A | XM_017024715.3 | c.8453G>A | p.Arg2818His | missense_variant | 45/64 | ||
MYO15A | XM_017024714.3 | c.8390G>A | p.Arg2797His | missense_variant | 44/63 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.8450G>A | p.Arg2817His | missense_variant | 47/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248334Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134944
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1460660Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 726682
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74478
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 | Jul 21, 2016 | The p.Arg2817His variant has been reported in 1 Asian individual with hearing lo ss who carried another variant of uncertain significance on the other allele (Gu 2015). It has also been identified in 2/8580 East Asian chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs76186108 0). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at positio n 2817 is not conserved in mammals or evolutionarily distant species. Of note, 1 mammal (Guinea pig) carries a histidine (His) at this position despite high nea rby amino acid conservation, raising the possibility that this change may be tol erated. Additional computational prediction tools suggest that the variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg2817His var iant is uncertain. - |
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 12, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 03, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2817 of the MYO15A protein (p.Arg2817His). This variant is present in population databases (rs761861080, gnomAD 0.01%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 24853665). ClinVar contains an entry for this variant (Variation ID: 505250). 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 not expected to disrupt MYO15A 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at