rs202189844
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP3BP6BS1
The NM_017433.5(MYO3A):c.585+4A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
MYO3A
NM_017433.5 splice_donor_region, intron
NM_017433.5 splice_donor_region, intron
Scores
1
1
Splicing: ADA: 0.9997
2
Clinical Significance
Conservation
PhyloP100: 1.36
Genes affected
MYO3A (HGNC:7601): (myosin IIIA) The protein encoded by this gene belongs to the myosin superfamily. Myosins are actin-dependent motor proteins and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as this one, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors. The protein encoded by this gene plays an important role in hearing in humans. Three different recessive, loss of function mutations in the encoded protein have been shown to cause nonsyndromic progressive hearing loss. Expression of this gene is highly restricted, with the strongest expression in retina and cochlea. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
BP6
?
Variant 10-26016900-A-T is Benign according to our data. Variant chr10-26016900-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178461.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr10-26016900-A-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00088 (134/152356) while in subpopulation AFR AF= 0.00284 (118/41592). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO3A | NM_017433.5 | c.585+4A>T | splice_donor_region_variant, intron_variant | ENST00000642920.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.585+4A>T | splice_donor_region_variant, intron_variant | NM_017433.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000854 AC: 130AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000270 AC: 68AN: 251436Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135890
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GnomAD4 exome AF: 0.000105 AC: 154AN: 1461602Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59AN XY: 727128
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GnomAD4 genome ? AF: 0.000880 AC: 134AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.000872 AC XY: 65AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2023 | In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 31, 2013 | 585+4A>T in intron 7 of MYO3A: This variant is not expected to have clinical sig nificance of because it has been identified in 0.2% (10/4406) of African America n chromosomes by the NHLBI Exome Sequencing Project and in 1% (3/314) of African chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; dbS NP rs202189844). In addition, this variant, which is located in the 5' splice re gion, is not in the invariant +1/+2 splice site positions and computational tool s do not predict an impact to splicing. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at