TSPAN17

Chr 5

tetraspanin 17

Also known as: FBX23, FBXO23, TM4SF17

NCBI Gene: 26262 ENSG00000048140 UniProt: Q96FV3 OMIM: 620446

The protein is a tetraspanin that regulates ADAM10 metalloprotease trafficking and substrate specificity, particularly affecting VE-cadherin expression in endothelial cells and leukocyte transmigration. This gene is not highly constrained against loss-of-function variants and has not been definitively associated with human disease. Mutations in TSPAN17 have not been established as a cause of pediatric neurological disorders.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the transmembrane 4 superfamily. It is characterized by four tetraspanin transmembrane segments. The function of this gene has not yet been determined. [provided by RefSeq, Mar 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.02

Clinical Summary— TSPAN17

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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

30 VUS of 48 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?

1.02LOEUF

pLI 0.000

Z-score 1.49

OE 0.63 (0.40–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.92Z-score

OE missense 0.81 (0.71–0.93)

158 obs / 194.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.40–1.02)

0≤0.351.4

Missense OE?0.81 (0.71–0.93)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 12 / 19.0Missense obs/exp: 158 / 194.2Syn Z: 0.25

This gene — mechanism propensity

0.84top 10%

GOF

0.83top 5%

LOF

0.1697th %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

48 submitted variants in ClinVar

ClinVar

Classification Summary

VUS30

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	30	0	30
Likely Benign	0	2	2
Benign	0	0	0
Total	30	2	32

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap TSPAN17 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →