TSPAN1

Chr 1

tetraspanin 1

Also known as: NET1, TM4C, TM4SF

NCBI Gene: 10103 ENSG00000117472 UniProt: O60635 OMIM: 613170

The TSPAN1 protein is a structural component of specialized membrane microdomains that regulate cell signaling, adhesion, and migration, and specifically facilitates neuronal differentiation by enhancing nerve growth factor receptor signaling. Loss-of-function mutations cause autosomal recessive intellectual disability with seizures and spasticity, typically presenting in early childhood. This gene is not highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.37

Clinical Summary— TSPAN1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

214 unique Pathogenic / Likely Pathogenic· 438 VUS of 1318 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.37LOEUF

pLI 0.000

Z-score 0.67

OE 0.79 (0.47–1.37)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.54Z-score

OE missense 0.87 (0.74–1.01)

113 obs / 130.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.79 (0.47–1.37)

0≤0.351.4

Missense OE?0.87 (0.74–1.01)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 9 / 11.4Missense obs/exp: 113 / 130.5Syn Z: -0.92

This gene — mechanism propensity

0.84top 10%

GOF

0.77top 25%

LOF

0.1299th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1318 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62

Likely Pathogenic152

VUS438

Likely Benign540

Benign23

Conflicting79

Pathogenic

152

Likely Pathogenic

438

VUS

540

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	5	3	1	62
Likely Pathogenic	124	24	4	0	152
VUS	14	367	43	14	438
Likely Benign	0	20	302	218	540
Benign	0	2	19	2	23
Conflicting	—				79
Total	191	418	371	235	1,294

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap TSPAN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →