rs72787346
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_017433.5(MYO3A):c.1559C>T(p.Ala520Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,612,384 control chromosomes in the GnomAD database, including 13 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 0.0021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0036 ( 13 hom. )
Consequence
MYO3A
NM_017433.5 missense
NM_017433.5 missense
Scores
5
5
4
Clinical Significance
Conservation
PhyloP100: 7.90
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.043385416).
BP6
?
Variant 10-26088402-C-T is Benign according to our data. Variant chr10-26088402-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45799.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}. Variant chr10-26088402-C-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00207 (316/152306) while in subpopulation NFE AF= 0.0037 (252/68028). AF 95% confidence interval is 0.00333. There are 0 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 13 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO3A | NM_017433.5 | c.1559C>T | p.Ala520Val | missense_variant | 15/35 | ENST00000642920.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.1559C>T | p.Ala520Val | missense_variant | 15/35 | NM_017433.5 | P1 | ||
MYO3A | ENST00000543632.5 | c.1559C>T | p.Ala520Val | missense_variant | 14/17 | 1 | |||
MYO3A | ENST00000642197.1 | n.1763C>T | non_coding_transcript_exon_variant | 15/27 | |||||
MYO3A | ENST00000647478.1 | c.1559C>T | p.Ala520Val | missense_variant, NMD_transcript_variant | 14/30 |
Frequencies
GnomAD3 genomes ? AF: 0.00208 AC: 316AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00221 AC: 554AN: 251114Hom.: 1 AF XY: 0.00225 AC XY: 306AN XY: 135778
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GnomAD4 exome AF: 0.00357 AC: 5213AN: 1460078Hom.: 13 Cov.: 31 AF XY: 0.00344 AC XY: 2496AN XY: 726506
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GnomAD4 genome ? AF: 0.00207 AC: 316AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | MYO3A: BS2 - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Ala520Val in Exon 15 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (27/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs72787346). - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 03, 2015 | - - |
Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
MYO3A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 14, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
D;D;D
Vest4
0.80, 0.77
MVP
0.93
MPC
0.25
ClinPred
T
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