rs727503315
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016239.4(MYO15A):c.7226del(p.Pro2409GlnfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,100 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 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
MYO15A
NM_016239.4 frameshift
NM_016239.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.31
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 17-18150440-GC-G is Pathogenic according to our data. Variant chr17-18150440-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 164548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.7226del | p.Pro2409GlnfsTer8 | frameshift_variant | 36/66 | ENST00000647165.2 | |
LOC124903944 | XR_007065652.1 | n.378-668del | intron_variant, non_coding_transcript_variant | ||||
MYO15A | XM_017024715.3 | c.7229del | p.Pro2410GlnfsTer8 | frameshift_variant | 34/64 | ||
MYO15A | XM_017024714.3 | c.7166del | p.Pro2389GlnfsTer8 | frameshift_variant | 33/63 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.7226del | p.Pro2409GlnfsTer8 | frameshift_variant | 36/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249480Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135376
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GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461844Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727236
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GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74458
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2022 | 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: 27344577, 34652575, 26226137) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Pro2409Glnfs*8) 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 (rs759151127, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 26226137). ClinVar contains an entry for this variant (Variation ID: 164548). For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 26, 2019 | The p.Pro2409fs variant in MYO15A has been previously reported by our laboratory in 3 individuals with hearing loss. Two of these individuals harbored a second pathogenic or likely pathogenic variant in MYO15A, and one individual was homozygous for the variant. It has also been identified in 0.008% (3/35356) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org/); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2409 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting. - |
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