chr17-18119933-TC-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016239.4(MYO15A):c.1137del(p.Tyr380MetfsTer64) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
MYO15A
NM_016239.4 frameshift
NM_016239.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.803
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 Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-18119933-TC-T is Pathogenic according to our data. Variant chr17-18119933-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 500061.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-18119933-TC-T is described in Lovd as [Likely_pathogenic]. Variant chr17-18119933-TC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.1137del | p.Tyr380MetfsTer64 | frameshift_variant | 2/66 | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.1137del | p.Tyr380MetfsTer64 | frameshift_variant | 2/66 | NM_016239.4 | P1 | ||
MYO15A | ENST00000583079.1 | n.770del | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000987 AC: 15AN: 151976Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000962 AC: 24AN: 249352Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135376
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GnomAD4 exome AF: 0.000142 AC: 207AN: 1461344Hom.: 0 Cov.: 36 AF XY: 0.000128 AC XY: 93AN XY: 726968
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Nov 24, 2017 | A heterozygous frameshift deletion variant, NM_016239.3(MYO15A):c.1137delC, has been identified in exon 2 of 66 of the MYO15A gene. This deletion is predicted to create a frameshift starting at amino acid position 380, introducing a stop codon 64 residues downstream, NP_057323.3(MYO15A):p.(Tyr380Metfs*64). This variant is predicted to result in loss of protein function either through truncation (loss of majority of the protein, including all functional domains) or nonsense-mediated decay. The variant is present in the gnomAD database at a frequency of 0.01% (28 heterozygotes) andhas been previously described as a compound heterozygote with a second truncating variant in two patients with hearing loss (Schrauwen, I., et al. (2013), Vona, B. et al. (2014)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | The MYO15A c.1137delC (p.Tyr380MetfsTer64) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has been reported in a compound heterozygous state along with a second null variant in three individuals with hearing loss (Schrauwen et al. 2013; Neveling et al. 2013; Vona et al. 2014). The individual identified in the Vona et al. (2014) study also carried the c.7C>G (p.Gln3Glu) missense variant in the MYH9 gene. The p.Tyr380MetfsTer64 variant was absent from nine normal hearing controls, but is reported at a frequency of 0.00038 in the European American population of the Exome Sequencing Project. Based on the evidence and due to the potential impact of frameshift variants, the p.Tyr380MetfsTer64 is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 15, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Tyr380Metfs*64) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs769260536, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with MYO15A-related conditions (PMID: 23208854, 24123792). This variant is also known as c.1134delC. ClinVar contains an entry for this variant (Variation ID: 500061). For these reasons, this variant has been classified as Pathogenic. - |
Nonsyndromic genetic hearing loss Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Mar 20, 2024 | The c.1137del (p.Tyr380fsTer64) variant in MYO15A is frameshift variant in biologically relevant exon 2/66 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.0.0 is 210/1179974 alleles (0.0001780 or 0.0178 %) in the European (non-Finnish) population (PM2_supporting, BS1, and BA1 not met). This variant has been detected in 3 individuals with nonsyndromic hearing loss. For each of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, but phase was not confirmed (p.Lys1003fsTer55, p.Glu209Ter, p.Arg3134Ter; PMIDs: 23208854, 28000701, 31980526; 1.5 pts. PM3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: (PVS1, PM3; Version 1; 3/20/2024). - |
Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PVS1_Very strong, PS1_Strong, PM2_Supporting, PP1_Supporting - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2020 | The p.Tyr380MetfsX64 variant in MYO15A has been previously reported in at least 3 individuals with hearing loss who were compound heterozygous for a second truncating MYO15A variant (Neveling 2013, Schrauwen 2013, Vona 2014, Zazo Seco 2017, Hou 2020). This variant has been identified in 0.02% (26/128476) of European chromosomes by gnomad chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 380 and leads to a premature termination codon 64 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYO15A gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at