10-25954875-A-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_017433.5(MYO3A):āc.170A>Cā(p.Asp57Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,611,934 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_017433.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO3A | NM_017433.5 | c.170A>C | p.Asp57Ala | missense_variant, splice_region_variant | 4/35 | ENST00000642920.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.170A>C | p.Asp57Ala | missense_variant, splice_region_variant | 4/35 | NM_017433.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000953 AC: 145AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000726 AC: 182AN: 250714Hom.: 1 AF XY: 0.000797 AC XY: 108AN XY: 135506
GnomAD4 exome AF: 0.00114 AC: 1659AN: 1459722Hom.: 3 Cov.: 31 AF XY: 0.00109 AC XY: 789AN XY: 726304
GnomAD4 genome AF: 0.000953 AC: 145AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64AN XY: 74430
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 57 of the MYO3A protein (p.Asp57Ala). This variant is present in population databases (rs146511800, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 45800). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 | Eurofins Ntd Llc (ga) | Mar 31, 2017 | - - |
Autosomal recessive nonsyndromic hearing loss 30 Uncertain:2
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 | Oct 31, 2018 | - - |
Hearing impairment Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Department of Otolaryngology ā Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PM2_Moderate, PP3_Strong - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2015 | The p.Asp57Ala variant in MYO3A has been previously identified by our laboratory in 3 individuals with hearing loss; however a second MYO3A variant was not dete cted in any of these individuals. It has also been identified in 0.1% (61/66602) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs146511800); however this frequency is not high enoug h to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this informat ion is not predictive enough to determine pathogenicity. In summary, the clinica l significance of the p.Asp57Ala variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 2021 | The c.170A>C (p.D57A) alteration is located in exon 4 (coding exon 2) of the MYO3A gene. This alteration results from a A to C substitution at nucleotide position 170, causing the aspartic acid (D) at amino acid position 57 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at