rs1193023501

chr11-17629159-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001292063.2(OTOG):c.6555G>A(p.Trp2185Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OTOG NM_001292063.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17629159-G-A is Pathogenic according to our data. Variant chr11-17629159-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517387.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6555G>A	p.Trp2185Ter	stop_gained	40/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6591G>A	p.Trp2197Ter	stop_gained	39/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6555G>A	p.Trp2185Ter	stop_gained	40/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6591G>A	p.Trp2197Ter	stop_gained	39/55	5		A2
OTOG	ENST00000342528.2	n.3893G>A		non_coding_transcript_exon_variant	16/22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000672 AC: 1 AN: 148878 Hom.: 0 AF XY: 0.0000125 AC XY: 1 AN XY: 80134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398064 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2017

The p.Trp2197X variant in OTOG has not been previously reported in individuals w ith hearing loss, but has been identified in 1/51754 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Althou gh this variant has been seen in the general population, its frequency is low en ough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 2197, which is predicted to l ead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schrader s 2012), and disruption of OTOG in mice resulted in deafness supporting a loss-o f-function mechanism for the disease (Simmler 2000). In summary, although additi onal evidence is required to strengthen the gene-disease association for OTOG an d hearing loss, the current data support that the p.Trp2197X variant is likely p athogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	39
Dann	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.69	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.35
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1193023501; hg19: chr11-17650706;