rs111033391
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_000260.4(MYO7A):c.3750+5G>A variant causes a splice region, 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
Consequence
NM_000260.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYO7A | ENST00000409709.9 | c.3750+5G>A | splice_region_variant, intron_variant | Intron 29 of 48 | 1 | NM_000260.4 | ENSP00000386331.3 | |||
MYO7A | ENST00000458637.6 | c.3750+5G>A | splice_region_variant, intron_variant | Intron 29 of 48 | 1 | ENSP00000392185.2 | ||||
MYO7A | ENST00000409619.6 | c.3717+5G>A | splice_region_variant, intron_variant | Intron 30 of 49 | 1 | ENSP00000386635.2 | ||||
MYO7A | ENST00000458169.2 | c.1293+5G>A | splice_region_variant, intron_variant | Intron 9 of 28 | 1 | ENSP00000417017.2 | ||||
MYO7A | ENST00000670577.1 | n.1590+5G>A | splice_region_variant, intron_variant | Intron 12 of 31 | ENSP00000499323.1 |
Frequencies
GnomAD3 genomes AF: 0.000644 AC: 98AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000746 AC: 119AN: 159564Hom.: 0 AF XY: 0.000623 AC XY: 53AN XY: 85058
GnomAD4 exome AF: 0.00143 AC: 2005AN: 1403360Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 930AN XY: 692896
GnomAD4 genome AF: 0.000643 AC: 98AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50AN XY: 74504
ClinVar
Submissions by phenotype
not provided Uncertain:5
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 been observed in individual(s) with deafness (PMID: 34515852). 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. -
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. -
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. -
BS1_supporting -
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not specified Uncertain:2
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. -
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Usher syndrome type 1B Uncertain:1
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Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at