rs897822685
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001292063.2(OTOG):c.4657G>T(p.Gly1553Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000778 in 1,542,482 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001292063.2 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.4657G>T | p.Gly1553Ter | stop_gained | 36/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.4693G>T | p.Gly1565Ter | stop_gained | 35/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.4657G>T | p.Gly1553Ter | stop_gained | 36/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.4693G>T | p.Gly1565Ter | stop_gained | 35/55 | 5 | A2 | ||
OTOG | ENST00000342528.2 | n.1995G>T | non_coding_transcript_exon_variant | 12/22 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000791 AC: 11AN: 1390450Hom.: 0 Cov.: 32 AF XY: 0.00000876 AC XY: 6AN XY: 684702
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74266
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 10655058, 23122587) - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | The p.Gly1565X variant in OTOG has not been previously reported in individuals w ith hearing loss or in large population databases. This nonsense variant leads t o a premature termination codon at position 1565, which is predicted to lead to a truncated or absent protein. Two loss of function variants in the OTOG gene ha ve been reported to segregate with hearing loss in two families (Schraders 2012) . Furthermore, disruption of Otog in mice results in deafness, supporting a loss -of-function mechanism for the disease (Simmler 2000). In summary, while the p.G ly1565X variant is likely pathogenic for autosomal recessive nonsyndromic hearin g loss based on the predicted impact of the variant, additional evidence support ing the role of OTOG in hearing loss is needed to definitively establish the cli nical significance of this variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at