rs772723774
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001378609.3(OTOGL):c.5341del(p.Ser1781LeufsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,460,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
OTOGL
NM_001378609.3 frameshift
NM_001378609.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.70
Genes affected
OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-80352367-CT-C is Pathogenic according to our data. Variant chr12-80352367-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 505326.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOGL | NM_001378609.3 | c.5341del | p.Ser1781LeufsTer24 | frameshift_variant | 45/59 | ENST00000547103.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOGL | ENST00000547103.7 | c.5341del | p.Ser1781LeufsTer24 | frameshift_variant | 45/59 | 5 | NM_001378609.3 | P1 | |
OTOGL | ENST00000646859.1 | c.5206del | p.Ser1736LeufsTer24 | frameshift_variant | 49/63 | ||||
OTOGL | ENST00000298820.7 | c.642del | p.Ser215LeufsTer24 | frameshift_variant | 6/18 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460174Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726420
GnomAD4 exome
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726420
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 08, 2016 | The p.Ser1772fs variant in OTOGL has not been previously reported in individuals with hearing loss, but has been identified in 1/65028 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 72723774). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 1772 and leads to a premature termination codon 24 amino acids downstream, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOGL gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner ba sed on the predicted impact of the variant. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at