TMTC4

Chr 13AR

transmembrane O-mannosyltransferase targeting cadherins 4

Also known as: DFNB122

NCBI Gene: 84899 ENSG00000125247 UniProt: Q5T4D3 OMIM: 618203

This gene encodes a transmembrane O-mannosyltransferase that transfers mannose residues to serine and threonine residues, particularly on cadherin superfamily proteins and other substrates like PDIA3. Autosomal recessive mutations cause deafness (DFNB122), though this association remains tentative based on current evidence. The gene shows low constraint to loss-of-function variation, consistent with recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane protein that belongs to family of proteins containing an N-terminal transmembrane domain and a C-terminal tetratricopeptide repeat (TPR) domain. TPR domains mediate protein-protein interactions in various cellular processes, such as synaptic vesicle fusion, protein folding, and protein translocation. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, Apr 2017]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Deafness, autosomal recessive 122MIM #620714

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.61

OE 0.54 (0.38–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.18Z-score

OE missense 0.98 (0.90–1.06)

428 obs / 438.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.38–0.78)

0≤0.351.4

Missense OE?0.98 (0.90–1.06)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 20 / 37.1Missense obs/exp: 428 / 438.9Syn Z: 0.04

Background carrier burden — how many people carry a rare variant somewhere in TMTC4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 59

935 rare PASS variants

Rare truncating (LoF)

1 in 1,600

145 rare PASS variants

Rare synonymous (reference)

1 in 110

401 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMTC4. 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 64	1 in 1,700
South Asian	~43k	1 in 47	1 in 1,300
Remaining (unassigned)	~30k	1 in 51	1 in 1,800
European (Finnish)	~27k	1 in 260	1 in 3,800
Admixed American	~22k	1 in 47	1 in 1,300
African / African American	~21k	1 in 43	1 in 550
East Asian	~20k	1 in 55	1 in 2,500
Ashkenazi Jewish	~13k	1 in 260	1 in 1,200
Middle Eastern	~2,884	1 in 42	none seen

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): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓