TOM1L2

Chr 17

target of myb1 like 2 membrane trafficking protein

ENSG00000175662 UniProt: Q6ZVM7 OMIM: 615519

The protein functions as a MYO6/Myosin VI adapter that targets myosin VI to endocytic structures and may recruit clathrin to endosomes during vesicular trafficking. TOM1L2 is located within the 3.7 Mb deletion of chromosome 17p11.2 associated with Smith-Magenis syndrome, which typically presents in early childhood with intellectual disability, behavioral problems, and distinctive facial features. Smith-Magenis syndrome follows an autosomal dominant inheritance pattern due to the chromosomal deletion.

OMIM ResearchSummary from RefSeq, UniProt

Acts as a MYO6/Myosin VI adapter protein that targets myosin VI to endocytic structures (PubMed:23023224). May also play a role in recruiting clathrin to endosomes (PubMed:16412388). May regulate growth factor-induced mitogenic signaling (PubMed:16479011)

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.56

Clinical Summary— TOM1L2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.002

Z-score 3.53

OE 0.34 (0.21–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.68Z-score

OE missense 0.89 (0.81–0.98)

280 obs / 313.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.21–0.56)

0≤0.351.4

Missense OE?0.89 (0.81–0.98)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 11 / 32.8Missense obs/exp: 280 / 313.8Syn Z: -0.73

This gene — mechanism propensity

0.7034th %ile

GOF

0.6932th %ile

LOF

0.2678th %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.