rs876657708
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_016239.4(MYO15A):c.9303+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_016239.4 splice_donor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.9303+1G>T | splice_donor_variant | ENST00000647165.2 | |||
MYO15A | XM_017024714.3 | c.9243+1G>T | splice_donor_variant | ||||
MYO15A | XM_017024715.3 | c.9306+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.9303+1G>T | splice_donor_variant | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 18, 2021 | DNA sequence analysis of the MYO15A gene demonstrated a sequence change in the canonical splice donor site of intron 55, c.9303+1G>T. This sequence change is predicted to disrupt the canonical splice donor site, and affect normal splicing of exon 55. The c.9303+1G>T change has not been previously described in individual with MYO15A-related disorder. This sequence change has not been described in the gnomAD population database. Collectively, this evidence suggests c.9303+1G>T is likely pathogenic, however, functional studies have not been performed to prove this conclusively. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2015 | The c.9303+1G>T variant in MYO15A has not been previously reported in individual s with hearing loss and was absent from large population studies. This variant o ccurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Lo ss-of-function variants in the MYO15A gene are an established disease mechanism for autosomal recessive hearing loss. In summary, this variant meets our criteri a to be classified as pathogenic for hearing loss in an autosomal recessive mann er (www.partners.org/personalizedmedicine/lmm), based on the predicted impact of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at