rs372466080
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP5BP4BP7
The NM_016239.4(MYO15A):c.9861C>T(p.Gly3287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,613,930 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016239.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.9861C>T | p.Gly3287= | synonymous_variant | 61/66 | ENST00000647165.2 | |
MYO15A | XM_017024715.3 | c.9864C>T | p.Gly3288= | synonymous_variant | 59/64 | ||
MYO15A | XM_017024714.3 | c.9801C>T | p.Gly3267= | synonymous_variant | 58/63 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.9861C>T | p.Gly3287= | synonymous_variant | 61/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000188 AC: 47AN: 249412Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135320
GnomAD4 exome AF: 0.0000869 AC: 127AN: 1461728Hom.: 0 Cov.: 33 AF XY: 0.0000921 AC XY: 67AN XY: 727166
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74358
ClinVar
Submissions by phenotype
not provided Pathogenic:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | MYO15A: BP4, BP7 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change affects codon 3287 of the MYO15A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYO15A protein. This variant is present in population databases (rs372466080, gnomAD 0.4%). This variant has been observed in individual(s) with non-syndromic deafness (PMID: 33111345, 33398081, 34733312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 33111345, 33398081, 34733312). ClinVar contains an entry for this variant (Variation ID: 45777). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 33398081). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2023 | Published functional studies suggest that this variant results in aberrant splicing and "skipping" of exon 61 (Hirsch et al., 2021); This variant is associated with the following publications: (PMID: 33398081, WangS2023[casereport], 33111345, 34733312) - |
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 | - | The MYO15A c.9861C>T:p.G3287G variant has been detected in our study, in 2 Jewish Ashkenazi families, in compound heterozygosity with another known Ashkenazi MYO15A mutation: c.8183G>A:p.R2728H. Following immediate application of our findings in the genetics clinics in Israel, 5 additional families were detected with full segregation of this variant in compound heterozygosity with a known MYO15A deafness variant. Compound heterozygosity has not been detected in none if the 23 hearing members in these families. MYO15A c.9861C>T is predicted to lead to loss of splicing enhancer motifs by 4 of 6 HSF algorithms and to lead to gain of silencer motifs by 2 of 6 algorithms. Skipping of MYO16A exon 61 would lead to a message deletion of 161bp and a premature stop at codon 3266 of 3531. - |
MYO15A-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 29, 2022 | The MYO15A c.9861C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Brownstein et al 2020. PubMed ID: 33111345; Hirsch et al 2021. PubMed ID: 33398081; Booth et al 2021. PubMed ID: 34733312). Functional in vitro studies have shown this variant results in exon skipping, a frameshift and premature termination (Hirsch et al 2021. PubMed ID: 33398081). This variant is reported in 0.41% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been described as a pathogenic founder variant in this population (http://gnomad.broadinstitute.org/variant/17-18069748-C-T; Brownstein et al 2020. PubMed ID: 33111345). This variant is interpreted as likely pathogenic. - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 22, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at