rs854778
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_016239.4(MYO15A):c.5826-12A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 1,610,714 control chromosomes in the GnomAD database, including 436,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.75 ( 43442 hom., cov: 30)
Exomes 𝑓: 0.73 ( 393105 hom. )
Consequence
MYO15A
NM_016239.4 splice_polypyrimidine_tract, intron
NM_016239.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001800
2
Clinical Significance
Conservation
PhyloP100: 0.446
Genes affected
MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 17-18142744-A-C is Benign according to our data. Variant chr17-18142744-A-C is described in ClinVar as [Benign]. Clinvar id is 45751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18142744-A-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.5826-12A>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000647165.2 | NP_057323.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.5826-12A>C | splice_polypyrimidine_tract_variant, intron_variant | NM_016239.4 | ENSP00000495481 | P1 |
Frequencies
GnomAD3 genomes AF: 0.753 AC: 114275AN: 151696Hom.: 43374 Cov.: 30
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GnomAD3 exomes AF: 0.717 AC: 175518AN: 244836Hom.: 63838 AF XY: 0.707 AC XY: 94074AN XY: 133036
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GnomAD4 exome AF: 0.732 AC: 1067674AN: 1458900Hom.: 393105 Cov.: 38 AF XY: 0.726 AC XY: 527027AN XY: 725620
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GnomAD4 genome AF: 0.754 AC: 114403AN: 151814Hom.: 43442 Cov.: 30 AF XY: 0.748 AC XY: 55535AN XY: 74212
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | 5826-12A>C in Intron 24 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 24.7% (1665/6752) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs854778). - |
Autosomal recessive nonsyndromic hearing loss 3 Benign:3
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at