GeneBe

OBSL1

protein-coding

obscurin like cytoskeletal adaptor 1, the group of I-set domain containing

Gene summary

Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

MANE transcript

NM_015311.3

Inheritance

AR

ClinVar variants

P:89U:741B:435

Top phenotype

Three M syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr2:219,550,728-219,571,859

External References & Databases

Ensembl (ENSG00000124006)NCBI Gene (23363)OMIM (610991)HGNC:29092GenCCUniProt (O75147)AlphaFoldClinVar (OBSL1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~21.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3M syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013039

Submitter: Labcorp Genetics (formerly Invitae)

3M syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013039

Submitter: PanelApp Australia

3-M syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007477

Submitter: Orphanet

3M syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013039

Submitter: Ambry Genetics

3M syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013039

Submitter: G2P

Clinical Genomic Database (CGD)

Three M syndrome 2AR

Manifestation: Craniofacial; Endocrine; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19481195; 23457316; 27796265Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OBSL1 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 1000
Inborn genetic diseasesTotal: 404
3M syndrome 2Total: 254
not specifiedTotal: 147
OBSL1-related disorderTotal: 51
Monogenic short statueTotal: 5
3M syndrome 1Total: 3
Fetal anomalies with a likely genetic causeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015311.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
25
clinvar
340
clinvar
20
clinvar
 386
missense
1
clinvar
680
clinvar
63
clinvar
7
clinvar
 751
nonsense
13
clinvar
10
clinvar
16
clinvar
2
clinvar
 41
start loss
1
clinvar
 1
frameshift
22
clinvar
25
clinvar
17
clinvar
1
clinvar
 65
splice donor/acceptor (+/-2bp)
16
clinvar
3
clinvar
2
clinvar
 21
Total3653741408271265

Highest pathogenic variant AF is 0.0003454124

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015311.3RefSeqNP_056126.121MANE Select
ENST00000404537.6EnsemblENSP00000385636.121MANE Select
NM_001173408.2RefSeqNP_001166879.19Standard
NM_001173431.2RefSeqNP_001166902.114Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Post-translational protein modification
  • Metabolism of proteins
  • Neddylation

Biological Process

  • microtubule cytoskeleton organization
  • muscle contraction
  • cytoskeleton organization
  • Golgi organization
  • regulation of mitotic nuclear division

Molecular Function

  • protein binding
  • cytoskeletal adaptor activity
  • structural constituent of muscle
  • actin filament binding
  • muscle alpha-actinin binding

Cellular Component

  • cytoplasm
  • Golgi apparatus
  • centrosome
  • cytosol
  • striated muscle thin filament

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000404537
Coding exons
21
Length
21131
Individuals with no LoFs
123979
Homozygous LoFs
2
Heterozygous LoFs
1160
Defined
125141
p
0.00465
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.0068511701.17e+30.9990.000077611872
Missense (PolyPhen)427426.771.00054414
Synonymous-0.1935175111.010.00003474136
Loss of Function2.425173.40.6950.00000410750

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0100.0095notable
Latino/Admixed American0.00640.0063notable
Ashkenazi Jewish0.0150.015notable
East Asian0.00280.0028notable
Finnish0.00420.0042notable
European (Non-Finnish)0.00370.0036notable
South Asian0.00160.0016notable
Other0.00670.0066notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: 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. {ECO:0000269|PubMed:21572988, ECO:0000269|PubMed:24793695, ECO:0000269|PubMed:24793696}.;

Intolerance Scores

LoFtool
0.861
RVIS EVS
-0.81
RVIS percentile EVS
12.02

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.831

Gene Damage Prediction

AllRecessiveDominant
MendelianHighMediumMedium
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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