OTOG

Chr 11AR

otogelin

Also known as: DFNB18B, MLEMP, OTGN

NCBI Gene: 340990 ENSG00000188162 UniProt: Q6ZRI0 OMIM: 604487

The protein encoded by OTOG is a glycoprotein component of the acellular membranes of the inner ear that anchors otoconial membranes and cupulae to underlying neuroepithelia and organizes the fibrillar network of the tectorial membrane in the cochlea. Mutations cause autosomal recessive nonsyndromic deafness type 18B, affecting hearing without other associated features. This gene shows tolerance to loss-of-function variants (low pLI score) and follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 18BMIM #614945

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · nonsyndromic genetic hearing loss · AR · ClinGen 2018

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.75

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 3.96

OE 0.62 (0.52–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.92Z-score

OE missense 0.87 (0.83–0.91)

1413 obs / 1630.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.52–0.75)

0≤0.351.4

Missense OE?0.87 (0.83–0.91)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 79 / 127.1Missense obs/exp: 1413 / 1630.8Syn Z: 2.64

Background carrier burden — how many people carry a rare variant somewhere in OTOG?

gnomAD v4 · ~699k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 9

4,302 rare PASS variants

Rare truncating (LoF)

1 in 170

623 rare PASS variants

Rare synonymous (reference)

1 in 19

1,684 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for OTOG. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~540k	1 in 13	1 in 180
South Asian	~40k	1 in 9	1 in 190
Remaining (unassigned)	~29k	1 in 9	1 in 140
European (Finnish)	~24k	1 in 41	1 in 670
African / African American	~21k	1 in 10	1 in 220
East Asian	~18k	1 in 11	1 in 190
Admixed American	~18k	1 in 10	1 in 180
Ashkenazi Jewish	~13k	1 in 46	1 in 780
Middle Eastern	~2,852	1 in 10	1 in 210

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 49 of 56 coding exons well covered in gnomAD exomes; exon 2 poorly covered; exons 1, 3, 6, 24, 34, 54 marginal. Genomes: all 56.? see exons ↓