rs794729637
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016239.4(MYO15A):c.3311dup(p.Glu1105Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K1102K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016239.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.3311dup | p.Glu1105Ter | frameshift_variant | 2/66 | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.3311dup | p.Glu1105Ter | frameshift_variant | 2/66 | NM_016239.4 | P1 | ||
MYO15A | ENST00000583079.1 | n.2944dup | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460544Hom.: 0 Cov.: 44 AF XY: 0.00000138 AC XY: 1AN XY: 726568
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change creates a premature translational stop signal (p.Glu1105*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 26969326, 29907799). ClinVar contains an entry for this variant (Variation ID: 203363). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2021 | Observed on the same allele (in cis) as another variant in the MYO15A gene in a patient with hearing loss in published literature (Sheppard et al., 2018); this variant in cis has been classified as benign at GeneDx; 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26969326, 29907799) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 25, 2021 | This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. - |
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jun 23, 2014 | The variant (c.3311dupG;p.E1105*) is a frameshift variant at amino acid position 1105 predicted to result in a truncated protein. It has not been reported, but another variant resulting in the same amino acid change, c.3313G>T;p.E1105*, has been reported in a patient with hearing loss (Nal et al. 2007, PMID: 17546645). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at