TM4SF5

Chr 17

transmembrane 4 L six family member 5

NCBI Gene: 9032 ENSG00000142484 UniProt: O14894 OMIM: 604657

TM4SF5 encodes a transmembrane glycoprotein that acts as a lysosomal membrane arginine sensor and forms complexes with mTOR and SLC38A9 to regulate mTORC1 activation and cell cycle progression. The gene shows low constraint against loss-of-function variants (pLI 0.008, LOEUF 0.97), and no definitive Mendelian diseases have been established from TM4SF5 mutations in current medical literature. Overexpression has been associated with tumor cell growth, but pathogenic germline variants causing pediatric neurological conditions have not been well-characterized.

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. This encoded protein is a cell surface glycoprotein and is highly similar in sequence and structure to transmembrane 4 superfamily member 1. It may play a role in cell proliferation, and overexpression of this protein may be associated with the uncontrolled growth of tumour cells. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.97

Clinical Summary— TM4SF5

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

23 VUS of 29 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?

0.97LOEUF

pLI 0.008

Z-score 1.64

OE 0.46 (0.24–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.79Z-score

OE missense 0.81 (0.69–0.95)

108 obs / 133.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.24–0.97)

0≤0.351.4

Missense OE?0.81 (0.69–0.95)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 5 / 10.8Missense obs/exp: 108 / 133.9Syn Z: 0.52

This gene — mechanism propensity

0.7133th %ile

GOF

0.80top 10%

LOF

0.2583th %ile

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

GOFprediction above median

DNprediction 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

29 submitted variants in ClinVar

ClinVar

Classification Summary

VUS23

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	23	23
Likely Benign	1	1
Benign	0	0
Total	24	24

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap TM4SF5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →