rs111033391
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000409709.9(MYO7A):c.3750+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,555,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 1 hom. )
Consequence
MYO7A
ENST00000409709.9 splice_donor_5th_base, intron
ENST00000409709.9 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 0.367
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYO7A | NM_000260.4 | c.3750+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000409709.9 | NP_000251.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYO7A | ENST00000409709.9 | c.3750+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000260.4 | ENSP00000386331 |
Frequencies
GnomAD3 genomes 0.000644 AC: 98AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000746 AC: 119AN: 159564Hom.: 0 AF XY: 0.000623 AC XY: 53AN XY: 85058
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GnomAD4 exome AF: 0.00143 AC: 2005AN: 1403360Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 930AN XY: 692896
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GnomAD4 genome 0.000643 AC: 98AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50AN XY: 74504
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2018 | The c.3750+5 G>A variant in the MYO7A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to reduce the quality of the splice donor site in intron 29, and is expected to cause abnormal gene splicing. The c.3750+5 G>A variant is observed in 125/185496 (0.0674%) alleles in large population cohorts (Lek et al., 2016). We interpret c.3750+5G>A as a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 31, 2022 | This sequence change falls in intron 29 of the MYO7A gene. It does not directly change the encoded amino acid sequence of the MYO7A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs111033391, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43220). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 22, 2021 | BS1_supporting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 21, 2017 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MYO7A c.3750+5G>A variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs111033391), ClinVar (classified as uncertain significance by four submitters with associated conditions of autosomal dominant and recessive deafness, type 11, and Usher syndrome type 1), and LOVD 3.0. The variant was identified in control databases in 131 of 190936 chromosomes at a frequency of 0.000686 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 97 of 79474 chromosomes (freq: 0.001221), European (Finnish) in 14 of 19312 chromosomes (freq: 0.000725), Other in 3 of 5524 chromosomes (freq: 0.000543), African in 7 of 17338 chromosomes (freq: 0.000404), Latino in 7 of 25308 chromosomes (freq: 0.000277), East Asian in 2 of 12954 chromosomes (freq: 0.000154) and South Asian in 1 of 22384 chromosomes (freq: 0.000045); it was not observed in the Ashkenazi Jewish population. The c.3750+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict the loss of the 5’ canonical splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 17, 2017 | The c.3750+5G>A variant in MYO7A has now been identified by our laboratory in 4 individuals with hearing loss, 2 of those also have retinal abnormalities. Howev er, a second variant in MYO7A was not found in any of them. This variant has bee n identified in 0.1% (93/76532) of European chromosomes and 0.07% (125/185496) o f total chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs111033391). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. This variant is located in the 5' splice region. Computational tools sugges t a possible impact to splicing. However, this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the c.3 750+5G>A variant is uncertain. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 11, 2023 | - - |
Usher syndrome type 1B Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 3
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at