ESPN

Chr 1ARAD

espin

Also known as: DFNA91, DFNB36, LP2654, USH1M

NCBI Gene: 83715 ENSG00000187017 UniProt: B1AK53 OMIM: 606351

This protein is a multifunctional actin-bundling protein that regulates the organization and dynamics of stereocilia in inner ear hair cells, which are essential for hearing and balance. Mutations cause autosomal recessive deafness (DFNB36), autosomal dominant deafness (DFNA91), and possibly Usher syndrome type 1M, which combines congenital deafness with progressive vision loss. The gene shows very low constraint against loss-of-function variants, and both recessive and dominant inheritance patterns are observed depending on the specific mutation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Usher syndrome, type 1MMIM #618632

Deafness, autosomal dominant 91MIM #621556

Deafness, autosomal recessive 36MIM #609006

ADAR

UniProtUsher syndrome 1M

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · nonsyndromic genetic hearing loss · AR · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.93

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.83

OE 0.63 (0.43–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.08Z-score

OE missense 1.01 (0.93–1.09)

440 obs / 435.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.43–0.93)

0≤0.351.4

Missense OE?1.01 (0.93–1.09)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 18 / 28.6Missense obs/exp: 440 / 435.4Syn Z: 0.80

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

1,695 rare PASS variants

Rare truncating (LoF)

1 in 300

264 rare PASS variants

Rare synonymous (reference)

1 in 53

799 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ESPN. 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)	~556k	1 in 30	1 in 350
South Asian	~43k	1 in 20	1 in 150
Remaining (unassigned)	~30k	1 in 18	1 in 190
European (Finnish)	~27k	1 in 57	1 in 430
Admixed American	~22k	1 in 21	1 in 290
African / African American	~21k	1 in 20	1 in 220
East Asian	~20k	1 in 25	1 in 160
Ashkenazi Jewish	~13k	1 in 120	1 in 510
Middle Eastern	~2,884	1 in 26	≈ 1 in 680

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 13 coding exons well covered in gnomAD exomes; exons 7, 8 marginal. Genomes: 12 of 13 (exon 7 below).? see exons ↓