rs564622720
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000260.4(MYO7A):c.18+2T>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 splice_donor
NM_000260.4 splice_donor
Scores
1
5
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.26
Genes affected
MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.009476534 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of -15, new splice context is: atgGTgatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11-77130654-T-A is Pathogenic according to our data. Variant chr11-77130654-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77130654-T-A is described in Lovd as [Likely_pathogenic]. Variant chr11-77130654-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.18+2T>A | splice_donor_variant | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.18+2T>A | splice_donor_variant | 1 | NM_000260.4 | ||||
MYO7A | ENST00000409619.6 | c.-96+2T>A | splice_donor_variant | 1 | |||||
MYO7A | ENST00000458637.6 | c.18+2T>A | splice_donor_variant | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246990Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134094
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460962Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726660
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74464
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2018 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 26, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with deafness (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 558377). This variant is present in population databases (rs564622720, ExAC 0.007%). This sequence change affects a donor splice site in intron 2 of the MYO7A 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 MYO7A are known to be pathogenic (PMID: 8900236, 25404053). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
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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