rs189910531
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001292063.2(OTOG):c.8125G>A(p.Asp2709Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00037 in 1,417,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001292063.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.8125G>A | p.Asp2709Asn | missense_variant | Exon 51 of 56 | 5 | NM_001292063.2 | ENSP00000382329.2 | ||
OTOG | ENST00000399391.7 | c.8161G>A | p.Asp2721Asn | missense_variant | Exon 50 of 55 | 5 | ENSP00000382323.2 |
Frequencies
GnomAD3 genomes AF: 0.000853 AC: 123AN: 144264Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000273 AC: 40AN: 146344Hom.: 0 AF XY: 0.000278 AC XY: 22AN XY: 79046
GnomAD4 exome AF: 0.000316 AC: 402AN: 1272990Hom.: 0 Cov.: 35 AF XY: 0.000299 AC XY: 187AN XY: 626408
GnomAD4 genome AF: 0.000852 AC: 123AN: 144368Hom.: 0 Cov.: 32 AF XY: 0.000986 AC XY: 69AN XY: 69950
ClinVar
Submissions by phenotype
not provided Uncertain:4
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2721 of the OTOG protein (p.Asp2721Asn). This variant is present in population databases (rs189910531, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 504840). 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: "Deleterious"; PolyPhen-2: "Possibly 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. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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Autosomal recessive nonsyndromic hearing loss 18B Uncertain:2
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not specified Uncertain:1
The p.Asp2721Asn variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 1/868 of African chromosomes and 1/272 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs189910531). Although this variant has been seen in t he general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide s trong support for or against an impact to the protein. In summary, the clinical significance of the p.Asp2721Asn variant is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at