rs201033926
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_017433.5(MYO3A):c.2275A>T(p.Asn759Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000578 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00061 ( 0 hom. )
Consequence
MYO3A
NM_017433.5 missense
NM_017433.5 missense
Scores
3
11
Clinical Significance
Conservation
PhyloP100: 4.10
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.165425).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO3A | NM_017433.5 | c.2275A>T | p.Asn759Tyr | missense_variant | 21/35 | ENST00000642920.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.2275A>T | p.Asn759Tyr | missense_variant | 21/35 | NM_017433.5 | P1 | ||
MYO3A | ENST00000543632.5 | c.1776+46778A>T | intron_variant | 1 | |||||
MYO3A | ENST00000642197.1 | n.2479A>T | non_coding_transcript_exon_variant | 21/27 | |||||
MYO3A | ENST00000647478.1 | c.*270A>T | 3_prime_UTR_variant, NMD_transcript_variant | 19/30 |
Frequencies
GnomAD3 genomes ? AF: 0.000282 AC: 43AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000251 AC: 63AN: 251124Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135740
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GnomAD4 exome AF: 0.000608 AC: 888AN: 1459762Hom.: 0 Cov.: 31 AF XY: 0.000595 AC XY: 432AN XY: 726324
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GnomAD4 genome ? AF: 0.000282 AC: 43AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74498
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 30 Uncertain:3
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Feb 09, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 19, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 759 of the MYO3A protein (p.Asn759Tyr). This variant is present in population databases (rs201033926, gnomAD 0.05%). 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: 164620). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MYO3A protein function with a negative predictive value of 80%. 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 | May 07, 2021 | Identified in a patient with bilateral sensorineural hearing loss who also harbored several other variants in different genes in published literature (Sheppard et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907799) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 12, 2014 | Variant classified as Uncertain Significance - Favor Benign. The p.Asn759Tyr var iant in MYO3A has been identified in three individuals with hearing loss, but no ne of them carries a second variant in the MYO3A gene (LMM unpublished data). Th is variant has also been identified in 0.06% (5/8600) of European American chrom osomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs201033926). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. The asparagi ne (Asn) at position 759 is moderately conserved in mammals and evolutionary dis tant species; however, several species of birds and reptiles carry a tyrosine (T yr) at this position, supporting that this change may be tolerated. Additional c omputational prediction tools suggest this variant may not impact the protein. I n summary, while the clinical significance of the p.Asn759Tyr variant is uncerta in, these data suggest that it is more likely to be benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
Polyphen
B;B
Vest4
0.33
MVP
0.82
MPC
0.083
ClinPred
T
GERP RS
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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