chr17-18119623-G-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_016239.4(MYO15A):āc.823G>Cā(p.Gly275Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,603,030 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275S) has been classified as Uncertain significance.
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.823G>C | p.Gly275Arg | missense_variant | 2/66 | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.823G>C | p.Gly275Arg | missense_variant | 2/66 | NM_016239.4 | P1 | ||
MYO15A | ENST00000583079.1 | n.456G>C | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.00151 AC: 230AN: 152022Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00146 AC: 349AN: 239140Hom.: 0 AF XY: 0.00149 AC XY: 196AN XY: 131316
GnomAD4 exome AF: 0.00248 AC: 3605AN: 1450890Hom.: 6 Cov.: 36 AF XY: 0.00236 AC XY: 1708AN XY: 722258
GnomAD4 genome AF: 0.00151 AC: 229AN: 152140Hom.: 1 Cov.: 33 AF XY: 0.00157 AC XY: 117AN XY: 74402
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | MYO15A: BP4 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 14, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2018 | Variant classified as Uncertain Significance - Favor Benign. The p.Gly275Arg var iant in MYO15A has been previously identified in 4 individuals with hearing loss , but none of these individuals had a pathogenic variant affecting the other cop y of the MYO15A and an alternate cause of hearing loss was identified in 2 (LMM data, Shearer 2013). This variant has been identified in 0.2% (123/63950) of Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs183969516) and is reported in ClinVar (Variation ID:1953 11). Computational prediction tools and conservation analysis suggest that the p .Gly275Arg variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, while the clinical signif icance of the p.Gly275Arg variant is uncertain, its frequency suggests that it i s more likely to be benign. ACMG/AMP Criteria applied: BP4. - |
Autosomal recessive nonsyndromic hearing loss 3 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. - |
MYO15A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 20, 2023 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at