rs886052676
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_016239.4(MYO15A):c.6863C>T(p.Ser2288Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000995 in 1,607,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S2288S) has been classified as Likely benign.
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.6863C>T | p.Ser2288Leu | missense_variant | 33/66 | ENST00000647165.2 | |
MYO15A | XM_017024715.3 | c.6866C>T | p.Ser2289Leu | missense_variant | 31/64 | ||
MYO15A | XM_017024714.3 | c.6803C>T | p.Ser2268Leu | missense_variant | 30/63 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.6863C>T | p.Ser2288Leu | missense_variant | 33/66 | NM_016239.4 | P1 | ||
MYO15A | ENST00000578999.1 | n.375C>T | non_coding_transcript_exon_variant | 3/4 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000852 AC: 2AN: 234646Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 127646
GnomAD4 exome AF: 0.00000687 AC: 10AN: 1455132Hom.: 0 Cov.: 34 AF XY: 0.00000277 AC XY: 2AN XY: 723176
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2023 | Identified with a second MYO15A variant (phase unknown) in patients with childhood-onset bilateral sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 35440622); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34974475, 35440622) - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 05, 2024 | The p.Ser2288Leu variant in MYO15A has been identified in the compound heterozygous state in at least 8 individuals with hearing loss (Wonkam 2022 PMID: 35440622, Chen 2022 PMID: 34974475, Wu 2022 PMID: 35982127, LMM internal data), 5 of whom had a second disease causing variant in the MYO15A gene, including 4 confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 322158) and has been identified in 0.005% (1/18344) East Asian chromosomes, 0.004% (1/22666) African chromosomes, and 0.004% (3/74792) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org/, v.4.0.0). This low frequency is consistent with the carrier frequency for recessive hearing loss. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS4_Supporting. - |
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1
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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at