chr17-18143580-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2
The NM_016239.4(MYO15A):c.5925G>A(p.Trp1975Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00086 in 1,560,974 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00090 ( 18 hom. )
Consequence
MYO15A
NM_016239.4 stop_gained
NM_016239.4 stop_gained
Scores
1
4
2
Clinical Significance
Conservation
PhyloP100: 3.20
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 Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
BS2
High Homozygotes in GnomAdExome4 at 18 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.5925G>A | p.Trp1975Ter | stop_gained | 26/66 | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.5925G>A | p.Trp1975Ter | stop_gained | 26/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000519 AC: 79AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00197 AC: 330AN: 167876Hom.: 2 AF XY: 0.00276 AC XY: 247AN XY: 89488
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GnomAD4 exome AF: 0.000897 AC: 1263AN: 1408684Hom.: 18 Cov.: 31 AF XY: 0.00125 AC XY: 868AN XY: 695766
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GnomAD4 genome AF: 0.000519 AC: 79AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50AN XY: 74472
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | MYO15A: BS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 04, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29907799, 22736430, 10552926, 27375115, 26969326, 30096381, 31130284) - |
Pathogenic, 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 | Invitae | Jan 29, 2024 | - - |
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 21, 2023 | - - |
Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jun 23, 2014 | The variant (c. 5925G>A;p.W1975*) is a nonsense variant, which is predicted to result in a truncated protein and considered pathogenic. - |
Rare genetic deafness Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Trp1975X variant in MYO15A has been reported in one Iranian individual with nonsyndromic hearing loss and segregated with disease in 6 family members, all of whom were homozygous for the variant (Fattahi 2012). However, this variant has also been identified in 1.7% (138/8086) of South Asian chromosomes including 2 individuals who were homozygous by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375290498). In addition, this nonsense variant introduces a premature codon at position 1975 in exon 26 of the MYO15A; exon 26 is missing in some alternatively spliced transcripts of MYO15A identified in the inner ear (Liang 1999), raising the possibility that this exon may not be functionally relevant. Although the segregation data reported in the Iranian family above (Fattahi 2012) suggests pathogenicity for this variant, it is not uncommon to detect homozygous variants in families with consanguinity and/or in isolated ethnic groups as is the case with this family, and it is possible that another variant on the same chromosome as this variant is causative for disease in the family. In summary, due to conflicting data, the clinical significance of the p.Trp1975X variant is uncertain.. ACMG/AMP Criteria applied: BA1. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at