rs376351191
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_016239.4(MYO15A):c.8050T>C(p.Tyr2684His) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,613,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y2684C) 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.8050T>C | p.Tyr2684His | missense_variant | 43/66 | ENST00000647165.2 | |
LOC105371567 | XR_001752809.1 | n.324A>G | non_coding_transcript_exon_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.8050T>C | p.Tyr2684His | missense_variant | 43/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000602 AC: 15AN: 249008Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135314
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461340Hom.: 0 Cov.: 40 AF XY: 0.0000303 AC XY: 22AN XY: 726976
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74332
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 29986705, 33398081, 34795337, 34733312) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2684 of the MYO15A protein (p.Tyr2684His). This variant is present in population databases (rs376351191, gnomAD 0.09%). This missense change has been observed in individual(s) with deafness (PMID: 26633542, 29986705; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 322166). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Oct 27, 2020 | Recessive, congenital SNHL - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 13, 2019 | The p.Tyr2684His variant in MYO15A has been previously reported in at least 3 individuals with hearing loss, one individual was compound heterozygous for a second likely pathogenic MYO15A, and one individual harbored a rare variant of uncertain significance that was confirmed in trans (Cabanillas 2018, Retterer 2015, Santos Serrao de Castro, 2012, LMM unpublished data). The variant has segregated in an affected sibling (Santos Serrao de Castro, 2012). This variant was identified in 0.07% (8/10344) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Tyr2684His variant is uncertain. ACMG/AMP criteria applied: PM3, PP1, PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at