11-77147796-A-G
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.133-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,608,948 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 Pathogenic (★★).
Frequency
Consequence
NM_000260.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.133-2A>G | splice_acceptor_variant | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.133-2A>G | splice_acceptor_variant | 1 | NM_000260.4 | ||||
MYO7A | ENST00000409619.6 | c.100-2A>G | splice_acceptor_variant | 1 | |||||
MYO7A | ENST00000458637.6 | c.133-2A>G | splice_acceptor_variant | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000830 AC: 2AN: 240926Hom.: 0 AF XY: 0.00000762 AC XY: 1AN XY: 131220
GnomAD4 exome AF: 0.0000453 AC: 66AN: 1456890Hom.: 0 Cov.: 34 AF XY: 0.0000387 AC XY: 28AN XY: 724194
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74284
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1997 | - - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 21, 2017 | - - |
Usher syndrome type 1B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 12, 2020 | - - |
MYO7A-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 12, 2020 | Variant summary: MYO7A c.133-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-06 in 240926 control chromosomes (gnomAD). c.133-2A>G has been reported in the literature in multiple compound heterozygous individuals affected with MYO7A-Related Disorders (Usher syndrome type 1; e.g. Liu_1997, LeQuesneStabej_2012, Bonnet_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change affects an acceptor splice site in intron 3 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with clinical features of autosomal recessive Usher syndrome and non-syndromic deafness (PMID: 9171832, 22135276, 24199935, 27460420, 31479088). This variant is also known as IVS3nt-2a>g. ClinVar contains an entry for this variant (Variation ID: 555778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at