DIAPH3

Chr 13

diaphanous related formin 3

Also known as: AN, AUNA1, DIA2, DRF3, NSDAN, diap3, mDia2

NCBI Gene: 81624 ENSG00000139734 UniProt: Q9NSV4

The protein is an actin nucleation and elongation factor that assembles F-actin structures and regulates cytokinesis, stress fiber formation, and transcriptional activation. Mutations cause autosomal dominant auditory neuropathy 1, affecting hearing function through damage to the auditory nerve pathway. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting tolerance to such mutations.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the diaphanous subfamily of the formin family. Members of this family are involved in actin remodeling and regulate cell movement and adhesion. Mutations in this gene are associated with autosomal dominant auditory neuropathy 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAuditory neuropathy, autosomal dominant 1

Clinical highlights

Gene–disease validity (ClinGen)

Limited · auditory neuropathy · AD · ClinGen 2020

not for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.74

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.000

Z-score 3.20

OE 0.56 (0.42–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.26Z-score

OE missense 0.97 (0.91–1.04)

605 obs / 623.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.42–0.74)

0≤0.351.4

Missense OE?0.97 (0.91–1.04)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 34 / 61.0Missense obs/exp: 605 / 623.1Syn Z: -0.86

Background carrier burden — how many people carry a rare variant somewhere in DIAPH3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

1,588 rare PASS variants

Rare truncating (LoF)

1 in 300

263 rare PASS variants

Rare synonymous (reference)

1 in 100

580 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DIAPH3. 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 49	1 in 300
South Asian	~43k	1 in 37	1 in 360
Remaining (unassigned)	~30k	1 in 34	1 in 330
European (Finnish)	~27k	1 in 120	1 in 830
Admixed American	~22k	1 in 41	1 in 230
African / African American	~21k	1 in 33	1 in 560
East Asian	~20k	1 in 38	1 in 210
Ashkenazi Jewish	~13k	1 in 300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 33	1 in 390

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): 25 of 28 coding exons well covered in gnomAD exomes; exons 2, 12, 17 marginal. Genomes: 27 of 28 (exon 25 below).? see exons ↓