OBSL1

Chr 2

obscurin like cytoskeletal adaptor 1

This gene encodes a cytoskeletal adaptor protein that functions as a core component of the 3M complex, which regulates microtubule dynamics and acts as a regulator of ubiquitin ligase pathways controlling Golgi morphogenesis and dendrite patterning in the brain. Biallelic mutations cause 3-M syndrome type 2, a growth disorder characterized by severe pre- and postnatal growth restriction with distinctive facial features, inherited in an autosomal recessive pattern. The gene shows very low constraint against loss-of-function variants in the general population.

ResearchSummary from RefSeq, OMIM, UniProt

Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695, PubMed:24793696). Acts as a regulator of the Cul7-RING(FBXW8) ubiquitin-protein ligase, playing a critical role in the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain. Required to localize CUL7 to the Golgi apparatus in neurons

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.88

Clinical Summary— OBSL1

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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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Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.42

OE 0.70 (0.55–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.01Z-score

OE missense 1.00 (0.95–1.05)

1170 obs / 1170.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.55–0.88)

0≤0.351.4

Missense OE?1.00 (0.95–1.05)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 51 / 73.4Missense obs/exp: 1170 / 1170.7Syn Z: -0.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveOBSL1-related 3-M syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6744th %ile

GOF

0.6736th %ile

LOF

0.3940th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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