TSPEAR

Chr 21AR

thrombospondin type laminin G domain and EAR repeats

Also known as: C21orf29, DFNB98, ECTD14, STHAG10, TSP-EAR

NCBI Gene: 54084 ENSG00000175894 UniProt: Q8WU66 OMIM: 612920

TSPEAR encodes a protein containing a thrombospondin-type laminin G domain that regulates Notch signaling during tooth and hair follicle morphogenesis and may function in auditory system development. Mutations cause autosomal recessive deafness-98, ectodermal dysplasia with abnormalities of hair, teeth, and nails, and selective tooth agenesis. The gene follows autosomal recessive inheritance and primarily affects ectodermal-derived structures including the inner ear, teeth, hair, and nails.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Deafness, autosomal recessive 98MIM #614861

Ectodermal dysplasia 14, hypohidrotic/hair/tooth/nail typeMIM #618180

Tooth agenesis, selective, 10MIM #620173

Clinical highlights

Gene–disease validity (ClinGen)

Disputed · nonsyndromic genetic hearing loss · AR · ClinGen 2024

evidence questions this relationship

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.20

LOEUF

—

Mechanism

📖

GeneReview available — TSPEAR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.000

Z-score 0.67

OE 0.87 (0.65–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.95Z-score

OE missense 1.13 (1.05–1.22)

473 obs / 418.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.87 (0.65–1.20)

0≤0.351.4

Missense OE?1.13 (1.05–1.22)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 28 / 32.1Missense obs/exp: 473 / 418.2Syn Z: -0.54

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,024 rare PASS variants

Rare truncating (LoF)

1 in 220

200 rare PASS variants

Rare synonymous (reference)

1 in 51

428 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TSPEAR. 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 44	1 in 190
South Asian	~43k	1 in 29	1 in 410
Remaining (unassigned)	~30k	1 in 34	1 in 250
European (Finnish)	~27k	1 in 88	1 in 760
Admixed American	~22k	1 in 35	1 in 430
African / African American	~21k	1 in 23	1 in 360
East Asian	~20k	1 in 54	1 in 520
Ashkenazi Jewish	~13k	1 in 150	1 in 2,200
Middle Eastern	~2,884	1 in 44	1 in 360

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): All 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓