11-17606135-G-A
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001292063.2(OTOG):c.4156G>A(p.Asp1386Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 34)
Consequence
OTOG
NM_001292063.2 missense, splice_region
NM_001292063.2 missense, splice_region
Scores
1
5
13
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.76
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.4156G>A | p.Asp1386Asn | missense_variant, splice_region_variant | 33/56 | ENST00000399397.6 | NP_001278992.1 | |
OTOG | NM_001277269.2 | c.4192G>A | p.Asp1398Asn | missense_variant, splice_region_variant | 32/55 | NP_001264198.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.4156G>A | p.Asp1386Asn | missense_variant, splice_region_variant | 33/56 | 5 | NM_001292063.2 | ENSP00000382329 | P2 | |
OTOG | ENST00000399391.7 | c.4192G>A | p.Asp1398Asn | missense_variant, splice_region_variant | 32/55 | 5 | ENSP00000382323 | A2 | ||
OTOG | ENST00000342528.2 | n.1494G>A | splice_region_variant, non_coding_transcript_exon_variant | 9/22 | 2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
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 | Apr 22, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1398As n variant in OTOG has not been previously reported in individuals with hearing l oss and data from large population studies is insufficient to assess the frequen cy of this variant. This variant is located in the last base of the exon, which is part of the 5? splice region. Computational tools suggest an impact to splici ng; however, this information is not predictive enough to determine pathogenicit y. In summary, while there is some suspicion for a pathogenic role, the clinica l significance of this variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;T
Vest4
MutPred
Loss of ubiquitination at K1400 (P = 0.0431);.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -34
Find out detailed SpliceAI scores and Pangolin per-transcript scores at