rs373462792
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_016239.4(MYO15A):c.8767C>T(p.Arg2923*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000112 in 1,608,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016239.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.8767C>T | p.Arg2923* | stop_gained | Exon 50 of 66 | ENST00000647165.2 | NP_057323.3 | |
MYO15A | XM_017024715.3 | c.8770C>T | p.Arg2924* | stop_gained | Exon 48 of 64 | XP_016880204.1 | ||
MYO15A | XM_017024714.3 | c.8707C>T | p.Arg2903* | stop_gained | Exon 47 of 63 | XP_016880203.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000824 AC: 12AN: 1455984Hom.: 0 Cov.: 32 AF XY: 0.00000829 AC XY: 6AN XY: 723756
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27375115, 30068307, 26242193, 26186295, 30579095, 32747562, 35440622, 23767834, 24949729) -
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2923*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 45771). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with deafness (PMID: 23767834). -
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1Uncertain:1
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Rare genetic deafness Pathogenic:1
The p.Arg2923X variant in MYO15A has been reported in three individuals with hea ring loss who were compound heterozygous or homozygous (Shafique 2014, Yang 2013 , LMM unpublished data). This variant has been identified in 1/5372 of East Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs373462792). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carri er frequency. This nonsense variant leads to a premature termination codon at po sition 2923, which is predicted to lead to a truncated or absent protein. Hetero zygous loss of function of the MYO15A gene is an established disease mechanism i n autosomal recessive nonsyndromic hearing loss. In summary, this variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedici ne/lmm). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at