TSPEAR

protein-coding

thrombospondin type laminin G domain and EAR repeats

Gene summary

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]

Previous symbols:

C21orf29
DFNB98

MANE transcript

NM_144991.3

Inheritance

ClinVar variants

P:91U:239B:146

Top phenotype

Deafness, autosomal recessive 98

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr21:44,497,893-44,711,572

External References & Databases

Ensembl (ENSG00000175894)

Transcript & Mutation Effects

hg38 • Region Span ~213.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ectodermal dysplasia 14, hair/tooth type with or without hypohidrosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032584

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 98LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013929

Submitter: Ambry Genetics

ectodermal dysplasia 14, hair/tooth type with or without hypohidrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032584

Submitter: G2P

ectodermal dysplasia 14, hair/tooth type with or without hypohidrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032584

Submitter: PanelApp Australia

tooth agenesis, selective, 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859339

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 98LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013929

Submitter: PanelApp Australia

ectodermal dysplasia 14, hair/tooth type with or without hypohidrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032584

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

*TSPEAR* was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2012 (Delmaghani et al., PMID: 22678063). At least 5 unique variants (3 frameshift, 1 nonsense, 1 silent variant in splice consensus sequence) have been reported in at least 4 probands in 4 publications (PMIDs: 22678063, 26969326, 34795337, 37561809). A frameshift variant that was reported in 2 probands and segregated in 2 additional family members (PMID: 22678063, 37561809) has also been reported in 2 families with ectodermal dysplasia and normal hearing (PMID: 27736875). Another nonsense variant that was observed as a homozygous variant in a proband was found to be heterozygous in the proband’s affected sibling and unaffected mother (PMID: 34795337). Moreover, a heterozygous missense variant with no second variant was reported in 1 proband (PMID: 30733538). This gene-disease relationship is supported by expression studies in murine cochlear tissue as well as functional alteration studies of null variants in non-patient cells (PMID: 22678063). Additionally, a *TSPEAR* K14-Cre knockdown revealed effects of *Tspear* knockdown in mice hair follicles and *NOTCH1* signaling but was not assessed for hearing loss (PMID: 27736875). In summary, the relationship between *TSPEAR* and autosomal recessive nonsyndromic hearing loss has been disputed. More evidence is needed to either support or refute the role *TSPEAR* plays in this disease. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 09/26/2017 as per SOP v6. It was reevaluated on 10/31/2024 using SOP v11. As a result of this reevaluation, this record underwent a review to be consistent with SOP v11. New case level evidence has been reviewed, but the classification did not change (PMIDs: 30733538, 34795337, 37561809).

autosomal recessive nonsyndromic hearing loss 98LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013929

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 98AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Dermatologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 22678063; 27736875; 30046887; 32112661; 34042254

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TSPEAR variants in ClinVar

13 Conditions Cataloged

not specifiedTotal: 983

not providedTotal: 526

Inborn genetic diseasesTotal: 144

TSPEAR-related disorderTotal: 101

Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosisTotal: 48

Tooth agenesis, selective, 10Total: 28

Autosomal recessive nonsyndromic hearing loss 98Total: 27

Ectodermal dysplasiaTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144991.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	108 clinvar	5 clinvar	118
missense	2 clinvar	19 clinvar	227 clinvar	31 clinvar	1 clinvar	280
nonsense	15 clinvar	10 clinvar	3 clinvar			28
start loss	1 clinvar					1
frameshift	19 clinvar	15 clinvar	2 clinvar			36
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	2 clinvar	1 clinvar		13
Total	40	51	239	140	6	476

Highest pathogenic variant AF is 0.000565193

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144991.3	RefSeq	NP_659428.2	12	MANE Select
ENST00000323084.9	Ensembl	ENSP00000321987.4	12	MANE Select
NM_001272037.2	RefSeq	NP_001258966.1	11	Standard
ENST00000642437.1	Ensembl	ENSP00000496535.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound

Molecular Function

molecular_function

Cellular Component

extracellular region
cell surface
stereocilium
ciliary membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000323084
Coding exons: 12
Length: 213721
Individuals with no LoFs: 125390
Homozygous LoFs: 1
Heterozygous LoFs: 357
Defined: 125748
p: 0.00142

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.952	473	418	1.13	0.0000274	4307
Missense (PolyPhen)		128	103.24	1.2399		1186
Synonymous	-0.540	201	191	1.05	0.0000143	1396
Loss of Function	0.675	28	32.1	0.872	0.00000177	318

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00076	0.00074	rare
Latino/Admixed American	0.00082	0.00081	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00087	0.00087	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.0023	0.0022	notable
South Asian	0.0011	0.0010	notable
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in development or function of the auditory system.;
Disease: DISEASE: Deafness, autosomal recessive, 98 (DFNB98) [MIM:614861]: A form of non-syndromic sensorineural hearing loss with prelingual onset. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:22678063}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.128

Intolerance Scores

RVIS EVS: -1.08
RVIS percentile EVS: 7.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium