rs183159689
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001378609.3(OTOGL):c.2564C>T(p.Pro855Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,613,152 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001378609.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOGL | NM_001378609.3 | c.2564C>T | p.Pro855Leu | missense_variant | Exon 24 of 59 | ENST00000547103.7 | NP_001365538.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOGL | ENST00000547103.7 | c.2564C>T | p.Pro855Leu | missense_variant | Exon 24 of 59 | 5 | NM_001378609.3 | ENSP00000447211.2 | ||
OTOGL | ENST00000646859.1 | c.2564C>T | p.Pro855Leu | missense_variant | Exon 29 of 63 | ENSP00000496036.1 |
Frequencies
GnomAD3 genomes AF: 0.00104 AC: 158AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000752 AC: 185AN: 246064Hom.: 0 AF XY: 0.000696 AC XY: 93AN XY: 133704
GnomAD4 exome AF: 0.000570 AC: 833AN: 1460954Hom.: 5 Cov.: 32 AF XY: 0.000572 AC XY: 416AN XY: 726770
GnomAD4 genome AF: 0.00103 AC: 157AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75AN XY: 74410
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 846 of the OTOGL protein (p.Pro846Leu). This variant is present in population databases (rs183159689, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 229115). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hearing impairment Uncertain:1
BP4_Supporting -
not specified Benign:1
The p.Pro846Leu variant in OTOGL is classified as likely benign because it has been identified in 0.18% (65/35176) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1_Supporting, BP4. -
OTOGL-related disorder Benign:1
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