rs754883697

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001292063.2(OTOG):​c.8541+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000871 in 1,550,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 splice_region, intron

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.12
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-17645648-G-A is Pathogenic according to our data. Variant chr11-17645648-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505108.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr11-17645648-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTOGNM_001292063.2 linkc.8541+5G>A splice_region_variant, intron_variant Intron 55 of 55 ENST00000399397.6 NP_001278992.1 H9KVB3
OTOGNM_001277269.2 linkc.8577+5G>A splice_region_variant, intron_variant Intron 54 of 54 NP_001264198.1 Q6ZRI0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOGENST00000399397.6 linkc.8541+5G>A splice_region_variant, intron_variant Intron 55 of 55 5 NM_001292063.2 ENSP00000382329.2 H9KVB3
OTOGENST00000399391.7 linkc.8577+5G>A splice_region_variant, intron_variant Intron 54 of 54 5 ENSP00000382323.2 Q6ZRI0-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152268
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000964
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000147
AC:
22
AN:
149252
Hom.:
0
AF XY:
0.000174
AC XY:
14
AN XY:
80378
show subpopulations
Gnomad AFR exome
AF:
0.000148
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000185
Gnomad SAS exome
AF:
0.000799
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000231
GnomAD4 exome
AF:
0.0000872
AC:
122
AN:
1398322
Hom.:
0
Cov.:
31
AF XY:
0.000110
AC XY:
76
AN XY:
689692
show subpopulations
Gnomad4 AFR exome
AF:
0.0000633
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000560
Gnomad4 SAS exome
AF:
0.000656
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000575
Gnomad4 OTH exome
AF:
0.0000517
GnomAD4 genome
AF:
0.0000853
AC:
13
AN:
152386
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74526
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 07, 2025Has not been previously published as pathogenic or benign to our knowledge; Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 21, 2024This sequence change falls in intron 54 of the OTOG gene. It does not directly change the encoded amino acid sequence of the OTOG protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs754883697, gnomAD 0.08%). This variant has been observed in individual(s) with clinical features of OTOG-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 505108). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 21, 2016The c.8577+5G>A variant in OTOG has not been previously reported in individuals with hearing loss. This variant has been identified in 0.4% (1/286) of Latino ch romosomes and in 0.1% (7/7640) of South Asian chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs754883697). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the c.8577+5G>A variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.22
CADD
Benign
22
DANN
Benign
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
SpliceAI score (max)
0.62
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.62
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754883697; hg19: chr11-17667195; API