chr10-26176849-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_017433.5(MYO3A):c.4438+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000204 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_017433.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.4438+4A>G | splice_region_variant, intron_variant | Intron 31 of 34 | NM_017433.5 | ENSP00000495965.1 | ||||
MYO3A | ENST00000543632.5 | c.1777-34994A>G | intron_variant | Intron 16 of 16 | 1 | ENSP00000445909.1 | ||||
MYO3A | ENST00000647478.1 | n.*1393+6310A>G | intron_variant | Intron 27 of 29 | ENSP00000493932.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251066Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135710
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461662Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727136
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change falls in intron 31 of the MYO3A gene. It does not directly change the encoded amino acid sequence of the MYO3A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756581092, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MYO3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 228984). 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. -
not specified Uncertain:1
The c.4438+4A>G variant in MYO3A has been previously reported by our laboratory in 1 individual with hearing loss. It has also been identified in 6/111362 Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org/; dbSNP rs756581092). Although this variant has been seen in the g eneral population, its frequency is not high enough to rule out a pathogenic rol e. This variant is located in the 5' splice region. Computational tools do not s uggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.4438+ 4G>A variant is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at