rs876657937
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001292063.2(OTOG):c.2276C>T(p.Ala759Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000982 in 1,528,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000087 ( 0 hom. )
Consequence
OTOG
NM_001292063.2 missense
NM_001292063.2 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 3.84
Genes affected
OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27346408).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.2276C>T | p.Ala759Val | missense_variant | 19/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.2312C>T | p.Ala771Val | missense_variant | 18/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.2276C>T | p.Ala759Val | missense_variant | 19/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.2312C>T | p.Ala771Val | missense_variant | 18/55 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000229 AC: 3AN: 130986Hom.: 0 AF XY: 0.0000421 AC XY: 3AN XY: 71284
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GnomAD4 exome AF: 0.00000872 AC: 12AN: 1375792Hom.: 0 Cov.: 32 AF XY: 0.0000118 AC XY: 8AN XY: 677462
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 20, 2015 | The p.Ala771Val variant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation a nalyses suggest that this variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, the clinic al significance of the p.Ala771Val variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.
REVEL
Benign
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Vest4
MutPred
Loss of disorder (P = 0.0604);.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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