rs199695398
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423128/MONDO:0019497/005
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.1582G>A | p.Gly528Ser | missense_variant | 2/66 | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.1582G>A | p.Gly528Ser | missense_variant | 2/66 | NM_016239.4 | P1 | ||
MYO15A | ENST00000583079.1 | n.1215G>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.000966 AC: 147AN: 152218Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000283 AC: 69AN: 243688Hom.: 0 AF XY: 0.000217 AC XY: 29AN XY: 133478
GnomAD4 exome AF: 0.000103 AC: 151AN: 1459018Hom.: 1 Cov.: 36 AF XY: 0.0000978 AC XY: 71AN XY: 725886
GnomAD4 genome ? AF: 0.000965 AC: 147AN: 152336Hom.: 1 Cov.: 33 AF XY: 0.00102 AC XY: 76AN XY: 74486
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2021 | The c.1582G>A (p.G528S) alteration is located in exon 2 (coding exon 1) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 1582, causing the glycine (G) at amino acid position 528 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 02, 2017 | p.Gly528Ser in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 3 mammals (naked mole-rat, chinchilla, and brush-tailed rat) have a serine (Ser) at this position despite high nearby amino acid sequence conservation. In addition, other computational tools do not suggest an impact to the protein. It has been identified in 0.3% (65/23654) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199695398). - |
MYO15A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 02, 2020 | 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). - |
Nonsyndromic genetic hearing loss Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jul 22, 2021 | The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at