17-18119978-AC-ACC
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016239.4(MYO15A):c.1185dup(p.Glu396ArgfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,612,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000027 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
MYO15A
NM_016239.4 frameshift
NM_016239.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.21
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-18119978-A-AC is Pathogenic according to our data. Variant chr17-18119978-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 228372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.1185dup | p.Glu396ArgfsTer36 | frameshift_variant | 2/66 | ENST00000647165.2 | NP_057323.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.1185dup | p.Glu396ArgfsTer36 | frameshift_variant | 2/66 | NM_016239.4 | ENSP00000495481 | P1 | ||
MYO15A | ENST00000583079.1 | n.818dup | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.0000265 AC: 4AN: 150760Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
4
AN:
150760
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000643 AC: 16AN: 248922Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135278
GnomAD3 exomes
AF:
AC:
16
AN:
248922
Hom.:
AF XY:
AC XY:
7
AN XY:
135278
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461298Hom.: 0 Cov.: 36 AF XY: 0.0000330 AC XY: 24AN XY: 726934
GnomAD4 exome
AF:
AC:
48
AN:
1461298
Hom.:
Cov.:
36
AF XY:
AC XY:
24
AN XY:
726934
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000265 AC: 4AN: 150872Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2AN XY: 73670
GnomAD4 genome
AF:
AC:
4
AN:
150872
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
73670
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnosis Center for Deafness | - | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Molecular Genetics, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine | Aug 28, 2019 | The individual with congenital NSHL carried single frameshift variant in MYO15A as well as single missense variant in the different locus in the same gene. They were segregated with the disease in his family and patient was a sporadic case in it. NSHL carried by the patient was categorized as a type of severe and profound hearing loss based on audiogram. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000228372 / PMID: 22245518 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 31, 2018 | A heterozygous frameshift duplication variant, NM_016239.3(MYO15A):c.1185dupC, has been identified in exon 2 of 66 of the MYO15A gene. This duplication is predicted to create a frameshift starting at amino acid position 396, introducing a stop codon 36 residues downstream (NP_057323.3(MYO15A):p.(Glu396Argfs*36)). This variant is predicted to result in loss of protein function either through truncation (including the loss of multiple domains) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.0047% (13 heterozygotes and 0 homozygotes). It has been previously described as pathogenic and segregated with disease in two families (Bashir R. et al. (2012), Miyagawa M. et al. (2015)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Glu396Argfs*36) 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 (rs746288259, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 22245518, 31827275). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228372). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2023 | Frameshift 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: 31589614, 37734845, 31827275, 33784549, 22245518, 35346193, 35248088) - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2016 | The p.Glu396fs variant in MYO15A has been previously reported in two individuals with hearing loss including one homozygote state and segregated with disease in 2 affected siblings (Bashir 2012, LMM data). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 396 and leads to a premature termination codon 36 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. In sum mary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner based on the predicted impact of the vari ant and segregation evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at