rs189947237
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_001292063.2(OTOG):c.1353C>A(p.Phe451Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,550,424 control chromosomes in the GnomAD database, including 3 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
Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 3 hom. )
Consequence
OTOG
NM_001292063.2 missense
NM_001292063.2 missense
Scores
1
1
16
Clinical Significance
Conservation
PhyloP100: -0.282
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 Likely_benign. Variant got -5 ACMG points.
BP6
Variant 11-17560719-C-A is Benign according to our data. Variant chr11-17560719-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450919.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr11-17560719-C-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.1353C>A | p.Phe451Leu | missense_variant | 13/56 | ENST00000399397.6 | NP_001278992.1 | |
OTOG | NM_001277269.2 | c.1389C>A | p.Phe463Leu | missense_variant | 12/55 | NP_001264198.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.1353C>A | p.Phe451Leu | missense_variant | 13/56 | 5 | NM_001292063.2 | ENSP00000382329.2 | ||
OTOG | ENST00000399391.7 | c.1389C>A | p.Phe463Leu | missense_variant | 12/55 | 5 | ENSP00000382323.2 | |||
OTOG | ENST00000498332.5 | n.1259C>A | non_coding_transcript_exon_variant | 12/16 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000414 AC: 63AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000623 AC: 93AN: 149342Hom.: 2 AF XY: 0.000622 AC XY: 50AN XY: 80390
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GnomAD4 exome AF: 0.000147 AC: 206AN: 1398170Hom.: 3 Cov.: 31 AF XY: 0.000132 AC XY: 91AN XY: 689624
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GnomAD4 genome AF: 0.000414 AC: 63AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74446
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 25, 2017 | p.Phe463Leu in exon 12 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 0.8% (95/11746) of East Asian chrom osomes including 2 homozygotes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs189947237). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2017 | The F463L variant in the OTOG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The F463L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F463L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals, however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret F463L as a variant of uncertain significance. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;T
Vest4
MutPred
Loss of catalytic residue at F463 (P = 0.1051);.;
MVP
ClinPred
T
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Varity_R
gMVP
Splicing
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Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -10
Find out detailed SpliceAI scores and Pangolin per-transcript scores at