rs763975867
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Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_016239.4(MYO15A):c.6764+2T>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000127 in 1,551,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
MYO15A
NM_016239.4 splice_donor
NM_016239.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.87
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 15 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
?
Variant 17-18148570-T-A is Pathogenic according to our data. Variant chr17-18148570-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289237.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=3, Uncertain_significance=1}. Variant chr17-18148570-T-A is described in Lovd as [Likely_pathogenic]. Variant chr17-18148570-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.6764+2T>A | splice_donor_variant | ENST00000647165.2 | |||
MYO15A | XM_017024714.3 | c.6704+2T>A | splice_donor_variant | ||||
MYO15A | XM_017024715.3 | c.6767+2T>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.6764+2T>A | splice_donor_variant | NM_016239.4 | P1 | ||||
MYO15A | ENST00000578999.1 | n.277-191T>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000790 AC: 12AN: 151970Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000194 AC: 3AN: 154764Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 81898
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GnomAD4 exome AF: 0.000132 AC: 185AN: 1399466Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 83AN XY: 690288
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2023 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24123792, 27375115, 26969326, 31827275, 32658404) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change affects a donor splice site in intron 32 of the MYO15A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs763975867, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with deafness (PMID: 24123792, 31827275). ClinVar contains an entry for this variant (Variation ID: 289237). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | MYO15A: PVS1, PM2, PM3 - |
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 19, 2017 | The MYO15A c.6764+2T>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in two studies and identified in two individuals with congenital hearing loss. One individual had the variant in a compound heterozygous state with a second splice variant (Sloan-Heggen et al. 2016). The other individual had the c.6764+2T>A variant along with two missense variants where phase was not determined (Neveling et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000083 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited clinical evidence and due to the potential impact of splice donor variants, the c.6764+2T>A variant is classified as a variant of unknown significance, but suspicious for pathogenicity for autosomal recessive hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 4-likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 3 (MIM#600316). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 12 heterozygotes, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are inconclusive. (I) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in individuals with hearing loss and confirmed to be compound heterozygous in two of these individuals (ClinVar; PMIDs: 24123792, 26969326). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 04, 2019 | The c.6764+2T>A variant in MYO15A has been reported in 3 individuals with hearin g loss (Neveling 2013, LMM data). However, only one of these individuals carried a second variant in MYO15A (Neveling 2013). The c.6764+2T>A variant has also be en identified in 0.0079% (6/75702) of European chromosomes by gnomAD (http://gno mad.broadinstitute.org). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. Loss of MYO15A function is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies ar e required to fully establish its clinical significance, the c.6764+2T>A variant meets criteria to be classified as likely pathogenic for autosomal recessive he aring loss. ACMG/AMP criteria applied: PVS1, PM2. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at