rs548172627
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000409709.9(MYO7A):c.471-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,798 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
ENST00000409709.9 splice_acceptor
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.471-1G>A | splice_acceptor_variant | ENST00000409709.9 | NP_000251.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.471-1G>A | splice_acceptor_variant | 1 | NM_000260.4 | ENSP00000386331 | ||||
MYO7A | ENST00000409619.6 | c.438-1G>A | splice_acceptor_variant | 1 | ENSP00000386635 | |||||
MYO7A | ENST00000458637.6 | c.471-1G>A | splice_acceptor_variant | 1 | ENSP00000392185 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249202Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135210
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461512Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727034
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74472
ClinVar
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 | Apr 06, 2018 | - - |
Usher syndrome type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomics, Clalit Research Institute, Clalit Health Care | - | Inheritance: The variant was identified in the Homozygous state in the sample (pm3_support. Frequency: The variant is rare, observed in 1 alleles out of 249,202 (0%) in the gnomAD reference population dataset. Frequency among cases: This variant has been observed in individuals with Usher syndrome type 1 (PMID: 18181211,PMID:25404053, etc.) (ps4). Variant type: Canonical splice site variant in a gene where loss of function is a known mechanism of disease (pvs1_strong) Clinical evidence: This variant has previously been described in ClinVar (VCV557808) with the following classifications: LP (2). Gene coverage: 100% of the MYO7A target region is covered with at least 10x. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2023 | This sequence change affects an acceptor splice site in intron 5 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). This variant is present in population databases (rs548172627, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with Usher syndrome type 1 (PMID: 18181211). ClinVar contains an entry for this variant (Variation ID: 557808). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1+PM2_Supporting+PM3_Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at