rs760980785
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_016239.4(MYO15A):c.6437G>A(p.Arg2146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,592 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).
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248620Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135148
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461592Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727114
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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: 32617096, 29849560, 30579064, 31579092, 34388253, 26242193, 26445815, 27375115, 33208113, 23865914) -
Rare genetic deafness Pathogenic:1
The p.Arg2146Gln variant in MYO15A has been reported in 1 Asian individual with autosomal recessive nonsyndromic hearing loss, and segregated with disease in 1 affected family member. Both siblings were compound heterozygous for this varian t and a reportedly pathogenic variant (c.4320+1G>A; Woo 2013). This variant has been identified in 1/65676 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs760980785). Although this var iant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools an d conservation analyses suggest that the p.Arg2146Gln variant may impact the pro tein, though this information alone is not predictive enough to determine pathog enicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -
not specified Uncertain:1
Variant summary: MYO15A c.6437G>A (p.Arg2146Gln) results in a conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248620 control chromosomes (gnomAD). c.6437G>A has been reported in the literature in compound heterozygous state in two siblings, who carried a likely pathogenic variant in trans, and were affected with profound, bilateral nonsyndromic hearing loss (Woo_2013), in addition the variant was also reported in heterozygous state (i.e. without specifying a variant in trans) in an individual with nonsyndromic hearing loss in the setting of a multigene panel testing (Sloan-Heggen_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at