rs150793986
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting
The NM_017433.5(MYO3A):āc.1525T>Cā(p.Tyr509His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00013 ( 0 hom., cov: 32)
Exomes š: 0.00013 ( 1 hom. )
Consequence
MYO3A
NM_017433.5 missense
NM_017433.5 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 8.01
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.819
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000134 (196/1461644) while in subpopulation MID AF= 0.00399 (23/5766). AF 95% confidence interval is 0.00273. There are 1 homozygotes in gnomad4_exome. There are 128 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO3A | NM_017433.5 | c.1525T>C | p.Tyr509His | missense_variant | 15/35 | ENST00000642920.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.1525T>C | p.Tyr509His | missense_variant | 15/35 | NM_017433.5 | P1 | ||
MYO3A | ENST00000543632.5 | c.1525T>C | p.Tyr509His | missense_variant | 14/17 | 1 | |||
MYO3A | ENST00000642197.1 | n.1729T>C | non_coding_transcript_exon_variant | 15/27 | |||||
MYO3A | ENST00000647478.1 | c.1525T>C | p.Tyr509His | missense_variant, NMD_transcript_variant | 14/30 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152236Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000227 AC: 57AN: 251294Hom.: 1 AF XY: 0.000287 AC XY: 39AN XY: 135836
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GnomAD4 exome AF: 0.000134 AC: 196AN: 1461644Hom.: 1 Cov.: 31 AF XY: 0.000176 AC XY: 128AN XY: 727120
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GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152354Hom.: 0 Cov.: 32 AF XY: 0.0000939 AC XY: 7AN XY: 74508
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 509 of the MYO3A protein (p.Tyr509His). This variant is present in population databases (rs150793986, gnomAD 0.07%). 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: 228976). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO3A protein function. 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 | GeneDx | Nov 15, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2017 | The p.Tyr509His variant in MYO3A has not been previously reported in individuals with hearing loss but has been identified in 10/16496 of South Asian chromosome s and 60/277060 all chromosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150793986). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analyses suggest that the p.Tyr509His variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Tyr509His variant is uncertain. ACMG/A MP criteria applied: PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;D
Vest4
0.94, 0.95
MVP
0.96
MPC
0.43
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at