rs146832858
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_017433.5(MYO3A):c.3729G>A(p.Arg1243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000582 in 1,609,764 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00069 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00057 ( 1 hom. )
Consequence
MYO3A
NM_017433.5 synonymous
NM_017433.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.958
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 -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant 10-26173993-G-A is Benign according to our data. Variant chr10-26173993-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227666.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr10-26173993-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.958 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO3A | NM_017433.5 | c.3729G>A | p.Arg1243= | synonymous_variant | 30/35 | ENST00000642920.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.3729G>A | p.Arg1243= | synonymous_variant | 30/35 | NM_017433.5 | P1 | ||
MYO3A | ENST00000543632.5 | c.1777-37850G>A | intron_variant | 1 | |||||
MYO3A | ENST00000647478.1 | c.*1393+3454G>A | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000690 AC: 105AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000493 AC: 122AN: 247290Hom.: 0 AF XY: 0.000553 AC XY: 74AN XY: 133778
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GnomAD4 exome AF: 0.000571 AC: 832AN: 1457510Hom.: 1 Cov.: 54 AF XY: 0.000572 AC XY: 415AN XY: 724924
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GnomAD4 genome ? AF: 0.000690 AC: 105AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | MYO3A: BP4, BP7 - |
Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1
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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 03, 2015 | p.Arg1243Arg in exon 30 of MYO3A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.1% (51/66154) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs146832858). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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