OBSL1

Summary

OBSL1 (obscurin like cytoskeletal adaptor 1, HGNC:29092) is a protein-coding gene on chromosome 2q35, encoding Obscurin-like protein 1 (O75147). Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity.

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.

Source: NCBI Gene 23363 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3M syndrome 2 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 1,499 total — 35 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 60
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_015311

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29092
Approved symbol	OBSL1
Name	obscurin like cytoskeletal adaptor 1
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0657
Ensembl gene	ENSG00000124006
Ensembl biotype	protein_coding
OMIM	610991
Entrez	23363

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 14 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000289656, ENST00000373873, ENST00000373876, ENST00000404537, ENST00000456147, ENST00000462385, ENST00000462534, ENST00000465149, ENST00000465589, ENST00000472388, ENST00000489804, ENST00000491370, ENST00000596474, ENST00000603926, ENST00000604031, ENST00000953544, ENST00000953545, ENST00000953546, ENST00000953547, ENST00000953548, ENST00000953549, ENST00000953550

RefSeq mRNA: 3 — MANE Select: NM_015311 NM_001173408, NM_001173431, NM_015311

CCDS: CCDS46520, CCDS54433, CCDS63134

Canonical transcript exons

ENST00000404537 — 21 exons

Exon	Start	End
ENSE00000843598	219556454	219556723
ENSE00000843603	219558184	219558459
ENSE00002303482	219550728	219550842
ENSE00003490894	219562402	219562674
ENSE00003496591	219568055	219568324
ENSE00003509468	219567718	219567969
ENSE00003521665	219552536	219552697
ENSE00003547456	219552868	219553024
ENSE00003567610	219556020	219556292
ENSE00003571469	219566830	219567126
ENSE00003600918	219552112	219552216
ENSE00003601837	219557823	219558110
ENSE00003606975	219551529	219551798
ENSE00003611749	219565242	219565514
ENSE00003615392	219563355	219563627
ENSE00003617585	219567273	219567575
ENSE00003652980	219554474	219554740
ENSE00003663724	219559225	219559497
ENSE00003679752	219553574	219553686
ENSE00003687919	219557343	219557618
ENSE00003843720	219570221	219571539

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.8498 / max 234.1131, expressed in 1584 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34102	8.7013	1505
34104	3.2915	1253
34103	2.9301	1197
34100	1.6127	797
34099	1.4040	688
34098	0.6116	384
34105	0.2877	142
34101	0.0108	3

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	99.46	gold quality
left testis	UBERON:0004533	99.45	gold quality
left ovary	UBERON:0002119	99.27	gold quality
right ovary	UBERON:0002118	99.23	gold quality
right lobe of thyroid gland	UBERON:0001119	98.82	gold quality
left lobe of thyroid gland	UBERON:0001120	98.75	gold quality
right adrenal gland cortex	UBERON:0035827	98.37	gold quality
right uterine tube	UBERON:0001302	98.36	gold quality
apex of heart	UBERON:0002098	98.34	gold quality
right adrenal gland	UBERON:0001233	98.28	gold quality
thyroid gland	UBERON:0002046	98.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.25	gold quality
right atrium auricular region	UBERON:0006631	98.17	gold quality
adenohypophysis	UBERON:0002196	98.13	gold quality
metanephros cortex	UBERON:0010533	98.12	gold quality
left uterine tube	UBERON:0001303	98.07	gold quality
left adrenal gland cortex	UBERON:0035825	98.00	gold quality
left adrenal gland	UBERON:0001234	97.96	gold quality
endocervix	UBERON:0000458	97.94	gold quality
cerebellar hemisphere	UBERON:0002245	97.86	gold quality
adrenal cortex	UBERON:0001235	97.79	gold quality
body of uterus	UBERON:0009853	97.76	gold quality
body of pancreas	UBERON:0001150	97.70	gold quality
cerebellar cortex	UBERON:0002129	97.68	gold quality
ventricular zone	UBERON:0003053	97.47	gold quality
adrenal tissue	UBERON:0018303	97.46	gold quality
testis	UBERON:0000473	97.30	gold quality
mucosa of stomach	UBERON:0001199	97.30	gold quality
pituitary gland	UBERON:0000007	97.25	gold quality
adrenal gland	UBERON:0002369	97.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	59.59
E-ANND-3	yes	10.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting OBSL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-874-5P	96.93	63.92	1014

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• report the cloning and characterization of OBSL1; OBSL1 is located on human chromosome 2q35 within 100 kb of SPEG, another gene related to obscurin (PMID:17289344)
• N-terminal Ig-domains of Obsl1 and Obscurin (Obsc) bind to titin-M10 and myomesin. Titin mutations, linked to limb-girdle muscular dystrophy 2J (LGMD2J) or Salih myopathy, weaken or abrogate titin-Obsc and titin-Obsl1 binding. (PMID:18477606)
• Loss of OBSL1 leads to downregulation of CUL7 and results in primordial growth disorder 3-M syndrome. (PMID:19481195)
• OBSL1 modulates the expression of IGFBP2 and IGFBP5 proteins in 3-M syndrome. (PMID:19877176)
• We propose that CUL7, OBSL1, and CCDC8 are members of a pathway controlling mammalian growth. (PMID:21737058)
• discussion of roles of OBSL1, CUL7 (cullin 7), and CCDC8 (coiled-coil domain containing protein 8) in growth and development using findings from patients with Miller-McKusick-Malvaux syndrome and Silver-Russell syndrome [REVIEW] (PMID:22156540)
• Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. (PMID:23018678)
• CUL7, OBSL1 and CCDC8 modulate the alternative splicing of the INSR (PMID:24711643)
• The CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development. (PMID:24793695)
• High-quality solution NMR structures of immunoglobulin-like domains 7 and 12 from human obscurin-like protein 1 were solved. The two domains share 30% sequence identity and their structures are, as expected, rather similar. (PMID:24989974)
• The cytoskeletal adaptor OBSL1 was discovered as a previously unrecognized interaction partner of the minor capsid protein L2 and was identified as a proviral host factor required for HPV16 endocytosis into target cells. (PMID:27654294)
• Data indicate that the patient has a homozygous mutation in obscurin like 1 obscurin-like protein 1 (OBSL1) gene, and that both of the parents had heterozygous mutations on OBSL1. (PMID:27796265)
• Crystal structure of the obscurin(-like-1):myomesin complex reveals a trans-complementation mechanism whereby an incomplete immunoglobulin-like domain assimilates an isoform-specific myomesin interdomain sequence. (PMID:27989621)
• The mutational spectrum of CUL7, OBSL1, and investigation of genotype-phenotype correlation in 3M syndrome has been reported. (PMID:30980518)
• Three M syndrome 2 in two Indian patients. (PMID:33135300)
• A rare cause of syndromic short stature: 3M syndrome in three families. (PMID:33258289)
• Natural history of facial and skeletal features from neonatal period to adulthood in a 3M syndrome cohort with biallelic CUL7 or OBSL1 variants. (PMID:34597859)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	obsl1a	ENSDARG00000003684
danio_rerio	obsl1b	ENSDARG00000077388
mus_musculus	Obsl1	ENSMUSG00000026211
rattus_norvegicus	Obsl1	ENSRNOG00000015346
drosophila_melanogaster	mtgo	FBGN0259735
caenorhabditis_elegans		WBGENE00007944

Paralogs (11): MYOM2 (ENSG00000036448), FNDC3B (ENSG00000075420), MYBPC2 (ENSG00000086967), MYOM1 (ENSG00000101605), FNDC3A (ENSG00000102531), MYBPH (ENSG00000133055), MYBPC3 (ENSG00000134571), MYOM3 (ENSG00000142661), IGSF22 (ENSG00000179057), MYBPC1 (ENSG00000196091), MYBPHL (ENSG00000221986)

Protein

Protein identifiers

Obscurin-like protein 1 — O75147 (reviewed: O75147)

All UniProt accessions (5): A6NN50, A8MSZ8, O75147, H0Y684, S4R463

UniProt curated annotations — full annotation on UniProt →

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. 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.

Subunit / interactions. Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1. Interacts with CCDC8. Interacts with CUL7; the interaction is direct. Interacts with FBXW8. Interacts (via N-terminal Ig-like domain) with TTN/titin (via C-terminal Ig-like domain); the interaction is direct.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Perinuclear region. Golgi apparatus.

Tissue specificity. Widely expressed, with predominant levels found in the heart.

Disease relevance. 3M syndrome 2 (3M2) [MIM:612921] An autosomal recessive disorder characterized by severe pre- and postnatal growth retardation, facial dysmorphism, large head circumference, and normal intelligence and endocrine function. Skeletal changes include long slender tubular bones and tall vertebral bodies. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
O75147-3	1	yes
O75147-2	2
O75147-1	3
O75147-4	4

RefSeq proteins (3): NP_001166879, NP_001166902, NP_056126* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR052385	Obscurin/Obscurin-like_Reg	Family

Pfam: PF07679, PF13927

UniProt features (102 total): strand 52, domain 15, disulfide bond 12, splice variant 7, sequence conflict 4, turn 3, region of interest 3, helix 3, chain 1, modified residue 1, mutagenesis site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3KNB	X-RAY DIFFRACTION	1.4
2WP3	X-RAY DIFFRACTION	1.48
2WWK	X-RAY DIFFRACTION	1.7
2WWM	X-RAY DIFFRACTION	2.3
5FM5	X-RAY DIFFRACTION	3.1
2CPC	SOLUTION NMR
2E6P	SOLUTION NMR
2E6Q	SOLUTION NMR
2LU7	SOLUTION NMR
2LVC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75147-F1	79.74	0.12

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 10

Disulfide bonds (12): 33–84, 149–209, 267–319, 362–412, 738–788, 829–879, 920–970, 1011–1061, 1103–1153, 1195–1245, 1381–1522, 1650–1700

Mutagenesis-validated functional residues (1):

Position	Phenotype
17	diminishes binding affinity for ttn.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 348 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEUROGENESIS, GOBP_CARDIAC_MYOFIBRIL_ASSEMBLY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, GOBP_ORGANELLE_FISSION

GO Biological Process (7): microtubule cytoskeleton organization (GO:0000226), cytoskeleton organization (GO:0007010), Golgi organization (GO:0007030), regulation of mitotic nuclear division (GO:0007088), protein localization to Golgi apparatus (GO:0034067), positive regulation of dendrite morphogenesis (GO:0050775), cardiac myofibril assembly (GO:0055003)

GO Molecular Function (2): cytoskeletal adaptor activity (GO:0008093), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centrosome (GO:0005813), cytosol (GO:0005829), intercalated disc (GO:0014704), Z disc (GO:0030018), M band (GO:0031430), perinuclear region of cytoplasm (GO:0048471), 3M complex (GO:1990393), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
organelle organization	2
cytoskeleton organization	1
microtubule-based process	1
endomembrane system organization	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
protein localization to organelle	1
positive regulation of cell morphogenesis	1
positive regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
positive regulation of neurogenesis	1
myofibril assembly	1
cardiac muscle cell development	1
cytoskeletal protein binding	1
protein-macromolecule adaptor activity	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
centriole	1
microtubule organizing center	1
cell-cell contact zone	1
I band	1
A band	1
protein-containing complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OBSL1	CUL7	Q14999	997
OBSL1	CCDC8	Q9H0W5	977
OBSL1	TTN	Q8WZ42	868
OBSL1	FBXW8	Q8N3Y1	820
OBSL1	FN1	P02751	655
OBSL1	C10orf71	Q711Q0	523
OBSL1	CD151	P48509	506
OBSL1	MMP15	P51511	496
OBSL1	PLEC	Q15149	486
OBSL1	CUL9	Q8IWT3	479
OBSL1	MYH6	P13533	477
OBSL1	IGFBP2	P18065	469
OBSL1	CAND1	Q86VP6	458
OBSL1	AHNAK	Q09666	454
OBSL1	VPS9D1	Q9Y2B5	447

IntAct

130 interactions, top by confidence:

A	B	Type	Score
MAPK14	OBSL1	psi-mi:“MI:0914”(association)	0.790
TTN	OBSL1	psi-mi:“MI:0915”(physical association)	0.780
TTN	OBSL1	psi-mi:“MI:0407”(direct interaction)	0.780
OBSL1	TTN	psi-mi:“MI:0407”(direct interaction)	0.780
POLR3GL	POLR3A	psi-mi:“MI:0914”(association)	0.730
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
PAK5	AURKA	psi-mi:“MI:0914”(association)	0.640
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
CAMKK2	OBSL1	psi-mi:“MI:0914”(association)	0.640
N	NOP56	psi-mi:“MI:0914”(association)	0.530
ALDH3B1	UBA6	psi-mi:“MI:0914”(association)	0.530
ZNF764	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
DNAAF8	CCDC85C	psi-mi:“MI:0914”(association)	0.530

BioGRID (1044): SEPT9 (Affinity Capture-MS), AAAS (Affinity Capture-MS), AATF (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), ABCF1 (Affinity Capture-MS), ACIN1 (Affinity Capture-MS), ACLY (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACTA1 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), ACTN1 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), ACTR2 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), ADAR (Affinity Capture-MS)

ESM2 similar proteins: A1A5C7, A6H7A0, B0BMW8, B0CM95, B0KWE9, B1MTH4, B2KI79, O43688, O62772, O75147, P0CK96, P35438, P35439, P52875, P57791, Q05586, Q28D01, Q2KJ29, Q3KNV8, Q3SZQ2, Q3UHH2, Q4L208, Q4V899, Q5R1P0, Q5R890, Q5SP67, Q5ZJ75, Q7TPB4, Q86YN1, Q8BTQ0, Q8C6G8, Q8C811, Q8R4D1, Q8VDI9, Q8VE98, Q90812, Q9BWV1, Q9D9E0, Q9H6U8, Q9H7D7

Diamond homologs: A0A087WV53, A2AAJ9, A2ASS6, A2RUH7, O75147, O94856, O94898, P05548, P52179, P54296, P97685, Q00872, Q23551, Q52KR2, Q5VST9, Q62234, Q80W87, Q810U3, Q8WX93, Q92626, A0A509AFG4, A0A5K1K8H0, A2ZVI7, A4IFM7, A8C984, A8WXF6, B9FKW9, C0HKC8, C0HKC9, E9PT87, O02827, O43293, O44997, O54784, O62305, O70150, O80673, O88764, O94768, P07313

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of TP53 Activity through Phosphorylation	9	12.2×	4e-05
Toll Like Receptor 3 (TLR3) Cascade	5	11.1×	6e-03
TRIF (TICAM1)-mediated TLR4 signaling	5	10.9×	6e-03
MyD88-independent TLR4 cascade	5	10.6×	6e-03
Mitochondrial biogenesis	5	9.7×	8e-03
VEGFA-VEGFR2 Pathway	6	9.6×	4e-03
Leishmania infection	5	9.4×	8e-03
Parasitic Infection Pathways	5	9.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1499 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	42
Uncertain significance	792
Likely benign	389
Benign	97

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1046	NM_015311.3(OBSL1):c.1149C>A (p.Cys383Ter)	Pathogenic
1047	NM_015311.3(OBSL1):c.1256_1265del (p.Arg419fs)	Pathogenic
1049	NM_015311.3(OBSL1):c.1465C>T (p.Arg489Ter)	Pathogenic
1072922	NM_015311.3(OBSL1):c.799dup (p.Cys267fs)	Pathogenic
1236172	NM_015311.3(OBSL1):c.2164del (p.Asp722fs)	Pathogenic
1333217	NM_015311.3(OBSL1):c.458dup (p.Leu154fs)	Pathogenic
1385927	NM_015311.3(OBSL1):c.1427C>A (p.Ser476Ter)	Pathogenic
1455612	NM_015311.3(OBSL1):c.135G>A (p.Trp45Ter)	Pathogenic
1456087	NM_015311.3(OBSL1):c.259del (p.Arg87fs)	Pathogenic
1687280	NM_015311.3(OBSL1):c.1068_1075dup (p.Val359fs)	Pathogenic
195306	NM_015311.3(OBSL1):c.1273dup (p.Thr425fs)	Pathogenic
2026486	NM_015311.3(OBSL1):c.2100_2122del (p.Gly701fs)	Pathogenic
2044173	NM_015311.3(OBSL1):c.691G>T (p.Glu231Ter)	Pathogenic
2426135	NC_000002.11:g.(?220415557)(220435954_?)del	Pathogenic
2426136	NC_000002.11:g.(?220434923)(220435954_?)del	Pathogenic
2572584	NM_015311.3(OBSL1):c.1260dup (p.Val421fs)	Pathogenic
2690347	NM_015311.3(OBSL1):c.1359dup (p.Glu454fs)	Pathogenic
2762103	NM_015311.3(OBSL1):c.2278G>T (p.Glu760Ter)	Pathogenic
2797165	NM_015311.3(OBSL1):c.1406del (p.Pro469fs)	Pathogenic
280285	NM_015311.3(OBSL1):c.1954del (p.Glu652fs)	Pathogenic
289410	NM_015311.3(OBSL1):c.1997_2049del (p.Gly666fs)	Pathogenic
2966811	NM_015311.3(OBSL1):c.1230C>G (p.Tyr410Ter)	Pathogenic
3585688	NM_015311.3(OBSL1):c.2249dup (p.Tyr750Ter)	Pathogenic
3646394	NM_015311.3(OBSL1):c.1035_1039dup (p.Leu347fs)	Pathogenic
3660984	NM_015311.3(OBSL1):c.2069_2075del (p.Asp690fs)	Pathogenic
3697270	NM_015311.3(OBSL1):c.1382G>A (p.Trp461Ter)	Pathogenic
3725147	NM_015311.3(OBSL1):c.655C>T (p.Gln219Ter)	Pathogenic
374349	NM_015311.3(OBSL1):c.2474del (p.Val825fs)	Pathogenic
3896354	NM_015311.3(OBSL1):c.103del (p.Val35fs)	Pathogenic
429882	NM_015311.3(OBSL1):c.2032C>T (p.Gln678Ter)	Pathogenic

SpliceAI

4130 predictions. Top by Δscore:

Variant	Effect	Δscore
2:219552538:T:TA	donor_gain	1.0000
2:219554746:C:CT	acceptor_gain	1.0000
2:219556018:A:AC	donor_gain	1.0000
2:219556019:C:CC	donor_gain	1.0000
2:219556019:CG:C	donor_gain	1.0000
2:219556019:CGCCT:C	donor_gain	1.0000
2:219556724:C:CC	acceptor_gain	1.0000
2:219562434:T:C	donor_gain	1.0000
2:219563387:T:C	donor_gain	1.0000
2:219566825:CCAA:C	donor_loss	1.0000
2:219566826:CAA:C	donor_loss	1.0000
2:219566828:A:AT	donor_loss	1.0000
2:219567127:C:CC	acceptor_gain	1.0000
2:219551794:CAATG:C	acceptor_gain	0.9900
2:219551795:AATG:A	acceptor_gain	0.9900
2:219551796:ATG:A	acceptor_gain	0.9900
2:219551797:TG:T	acceptor_gain	0.9900
2:219551799:C:CC	acceptor_gain	0.9900
2:219552110:AC:A	donor_gain	0.9900
2:219552110:ACCCT:A	donor_gain	0.9900
2:219552111:CC:C	donor_gain	0.9900
2:219552111:CCCTC:C	donor_gain	0.9900
2:219552120:T:TA	donor_gain	0.9900
2:219554653:T:TA	donor_gain	0.9900
2:219554737:CTCG:C	acceptor_gain	0.9900
2:219554739:CG:C	acceptor_gain	0.9900
2:219554741:C:CC	acceptor_gain	0.9900
2:219554746:C:T	acceptor_gain	0.9900
2:219554747:G:T	acceptor_gain	0.9900
2:219556015:CTCA:C	donor_loss	0.9900

AlphaMissense

12127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:219568220:A:G	W373R	1.000
2:219568220:A:T	W373R	1.000
2:219570264:G:C	N323K	1.000
2:219570264:G:T	N323K	1.000
2:219570396:C:A	W279C	1.000
2:219570396:C:G	W279C	1.000
2:219570398:A:G	W279R	1.000
2:219570398:A:T	W279R	1.000
2:219570439:A:G	F265S	1.000
2:219562564:A:G	W931R	0.999
2:219562564:A:T	W931R	0.999
2:219567871:A:G	W461R	0.999
2:219567871:A:T	W461R	0.999
2:219568109:A:C	Y410D	0.999
2:219568147:A:G	L397P	0.999
2:219570232:A:G	L334P	0.999
2:219570276:G:C	C319W	0.999
2:219570278:A:G	C319R	0.999
2:219570284:A:C	Y317D	0.999
2:219570306:G:C	C309W	0.999
2:219570322:A:G	L304P	0.999
2:219570397:C:G	W279S	0.999
2:219570409:G:T	P275H	0.999
2:219570422:C:G	G271R	0.999
2:219570434:A:G	C267R	0.999
2:219570445:G:T	A263D	0.999
2:219570989:A:C	Y82D	0.999
2:219571098:C:A	W45C	0.999
2:219571098:C:G	W45C	0.999
2:219571100:A:G	W45R	0.999

dbSNP variants (sampled 300 via entrez): RS1000043732 (2:219560621 G>A), RS1000045071 (2:219554827 A>C,G), RS1000161913 (2:219557691 C>T), RS1000177545 (2:219563002 G>C), RS1000286728 (2:219564775 AAAAG>A,AAAAGAAAG,AAAAGAAAGAAAG), RS1000456736 (2:219552757 C>T), RS1000489044 (2:219556801 G>A,T), RS1000540037 (2:219550885 G>A,C,T), RS1000603324 (2:219570071 T>TGA), RS1000662962 (2:219566560 A>G), RS1000712463 (2:219562793 G>A,C), RS1000907726 (2:219571804 C>T), RS1000911445 (2:219562044 A>G), RS1000914991 (2:219555731 C>G,T), RS1001288142 (2:219566080 T>C)

Disease associations

OMIM: gene MIM:610991 | disease phenotypes: MIM:612921, MIM:273750

GenCC curated gene-disease

Disease	Classification	Inheritance
3M syndrome 2	Definitive	Autosomal recessive
3-M syndrome	Supportive	Autosomal recessive

Mondo (3): 3M syndrome 2 (MONDO:0013039), 3M syndrome 1 (MONDO:0010117), 3-M syndrome (MONDO:0007477)

Orphanet (1): 3M syndrome (Orphanet:2616)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000144	Decreased fertility
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000307	Pointed chin
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000574	Thick eyebrow
HP:0000682	Abnormal dental enamel morphology
HP:0000684	Delayed eruption of teeth
HP:0000689	Dental malocclusion
HP:0000768	Pectus carinatum
HP:0000883	Thin ribs
HP:0000888	Horizontal ribs
HP:0000944	Abnormal metaphysis morphology
HP:0001374	Congenital hip dislocation
HP:0001382	Joint hypermobility
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001838	Rocker bottom foot
HP:0002007	Frontal bossing
HP:0002650	Scoliosis

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535314	Miller-McKusick-Malvaux-Syndrome (3M Syndrome) (supp.)
C567862	Three M Syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

63 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	6
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
Acetaminophen	decreases expression	3
bisphenol A	affects expression, increases expression	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
glycidyl methacrylate	decreases expression	1
potassium perchlorate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coumarin	decreases phosphorylation	1
cupric oxide	decreases expression	1
pentanal	increases expression	1
avobenzone	increases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
entinostat	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.