rs149813580
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting
This summary comes from the ClinGen Evidence Repository: The p.Glu1499Asp variant in MYO15A has been identified in the heterozygous state in at least 4 individuals with hearing loss, 1 individual with intrauterine demise, and in 1 individual with hearing loss with a variant of uncertain significance suspected in trans (Partners LMM internal data SCV000711130.2, PMIDs: 27068579, 32304219). The filtering allele frequency (the lower threshold of the 95% CI of 59/35358) of the p.Glu1499Asp variant in the MYO15A gene is 0.13% for Latino/Admixed chromosomes by gnomAD v2.1, 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). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423917/MONDO:0019497/005
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.4497G>T | p.Glu1499Asp | missense_variant | 13/66 | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.4497G>T | p.Glu1499Asp | missense_variant | 13/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000480 AC: 73AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000798 AC: 199AN: 249272Hom.: 2 AF XY: 0.000717 AC XY: 97AN XY: 135304
GnomAD4 exome AF: 0.00108 AC: 1577AN: 1461830Hom.: 3 Cov.: 31 AF XY: 0.00105 AC XY: 762AN XY: 727212
GnomAD4 genome ? AF: 0.000479 AC: 73AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74480
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 03, 2021 | - - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2021 | Reported in a patient with hearing loss in published literature; however, clinical information was limited (Sommen M et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27068579, 32304219) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2019 | The p.Glu1499Asp variant in MYO15A has been identified in at least 5 individuals with hearing loss, only 1 of whom carried a second variant (classified as a VUS) in MYO15A (Sommen 2016, LMM data). This variant has also been identified in 0.17% (59/35358) of Latino and 0.11% (141/128518) of European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu1499Asp variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting, PP3. - |
Nonsyndromic genetic hearing loss Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jun 15, 2021 | The p.Glu1499Asp variant in MYO15A has been identified in the heterozygous state in at least 4 individuals with hearing loss, 1 individual with intrauterine demise, and in 1 individual with hearing loss with a variant of uncertain significance suspected in trans (Partners LMM internal data SCV000711130.2, PMIDs: 27068579, 32304219). The filtering allele frequency (the lower threshold of the 95% CI of 59/35358) of the p.Glu1499Asp variant in the MYO15A gene is 0.13% for Latino/Admixed chromosomes by gnomAD v2.1, 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). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting. - |
MYO15A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 29, 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at