rs548496846

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001292063.2(OTOG):​c.7693+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,540,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 0.00087 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 0.9999
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:6

Conservation

PhyloP100: 7.66
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 4 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012239762 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OTOGNM_001292063.2 linkuse as main transcriptc.7693+1G>A splice_donor_variant, intron_variant ENST00000399397.6 NP_001278992.1 H9KVB3
OTOGNM_001277269.2 linkuse as main transcriptc.7729+1G>A splice_donor_variant, intron_variant NP_001264198.1 Q6ZRI0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OTOGENST00000399397.6 linkuse as main transcriptc.7693+1G>A splice_donor_variant, intron_variant 5 NM_001292063.2 ENSP00000382329.2 H9KVB3
OTOGENST00000399391.7 linkuse as main transcriptc.7729+1G>A splice_donor_variant, intron_variant 5 ENSP00000382323.2 Q6ZRI0-1
OTOGENST00000342528.2 linkuse as main transcriptn.4606-422G>A intron_variant 2

Frequencies

GnomAD3 genomes
AF:
0.000875
AC:
133
AN:
152072
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000266
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00168
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.000697
AC:
95
AN:
136276
Hom.:
0
AF XY:
0.000634
AC XY:
47
AN XY:
74082
show subpopulations
Gnomad AFR exome
AF:
0.000156
Gnomad AMR exome
AF:
0.0000823
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00173
Gnomad NFE exome
AF:
0.00143
Gnomad OTH exome
AF:
0.000492
GnomAD4 exome
AF:
0.00151
AC:
2090
AN:
1387974
Hom.:
0
Cov.:
33
AF XY:
0.00142
AC XY:
969
AN XY:
684660
show subpopulations
Gnomad4 AFR exome
AF:
0.000190
Gnomad4 AMR exome
AF:
0.000113
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00149
Gnomad4 NFE exome
AF:
0.00184
Gnomad4 OTH exome
AF:
0.000675
GnomAD4 genome
AF:
0.000874
AC:
133
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.000672
AC XY:
50
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000565
Gnomad4 NFE
AF:
0.00168
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.00140
Hom.:
1
Bravo
AF:
0.000854
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00337
AC:
13
ExAC
AF:
0.000549
AC:
12

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:3Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023OTOG: PVS1:Moderate, BS1:Supporting -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 03, 2024Observed without another OTOG variant in a patient with hearing loss in published literature (PMID: 29196752); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29196752) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 25, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024This sequence change affects a donor splice site in intron 45 of the OTOG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs548496846, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 29196752). ClinVar contains an entry for this variant (Variation ID: 488980). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Autosomal recessive nonsyndromic hearing loss 18B Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 25, 2022- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 06, 2018Variant classified as Uncertain Significance - Favor Pathogenic. The c.7729+1G>A variant in OTOG has been reported in the heterozygous state in one individual w ith hearing loss (Baux 2017) and has been identified by our laboratory in the he terozygous state in 2 individuals with hearing loss, both of whom had pathogenic variants in other genes sufficient to explain their hearing loss. This variant has also been identified in 0.2% (101/60880) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs5484 96846). Although this variant has been seen in the general population, its frequ ency is not high enough to rule out a pathogenic role. This variant occurs in th e invariant region (+/- 1,2) of the splice consensus sequence of exon 45; howeve r, exon 45 is in-frame and it is unclear if altered splicing will lead to an in- frame deletion of exon 45 or an absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.7729+1G>A va riant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
28
DANN
Uncertain
0.99
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.97
D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.95
Position offset: -1

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: rs548496846; hg19: chr11-17656735; COSMIC: COSV61127486; API