11-17559660-A-G
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_001292063.2(OTOG):āc.1340A>Gā(p.Asn447Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000444 in 1,550,190 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0022 ( 2 hom., cov: 32)
Exomes š: 0.00025 ( 0 hom. )
Consequence
OTOG
NM_001292063.2 missense, splice_region
NM_001292063.2 missense, splice_region
Scores
5
14
Splicing: ADA: 0.1068
2
Clinical Significance
Conservation
PhyloP100: 4.85
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 Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.010245383).
BP6
Variant 11-17559660-A-G is Benign according to our data. Variant chr11-17559660-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 504781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.1340A>G | p.Asn447Ser | missense_variant, splice_region_variant | 12/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.1376A>G | p.Asn459Ser | missense_variant, splice_region_variant | 11/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.1340A>G | p.Asn447Ser | missense_variant, splice_region_variant | 12/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.1376A>G | p.Asn459Ser | missense_variant, splice_region_variant | 11/55 | 5 | A2 | ||
OTOG | ENST00000498332.5 | n.1246A>G | splice_region_variant, non_coding_transcript_exon_variant | 11/16 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00217 AC: 330AN: 152036Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000474 AC: 71AN: 149798Hom.: 0 AF XY: 0.000348 AC XY: 28AN XY: 80468
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GnomAD4 exome AF: 0.000252 AC: 353AN: 1398038Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 140AN XY: 689526
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GnomAD4 genome AF: 0.00221 AC: 336AN: 152152Hom.: 2 Cov.: 32 AF XY: 0.00211 AC XY: 157AN XY: 74388
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 19, 2021 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | Asn459Ser in exon 11 of OTOG: This variant is not expected to have clinical sign ificance because it has been identified in 3.1% (6/194) of Luhya (Kenyan) chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs115772736). - |
OTOG-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 20, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at