LMBRD1

Summary

LMBRD1 (LMBR1 domain containing 1, HGNC:23038) is a protein-coding gene on chromosome 6q13, encoding Lysosomal cobalamin transport escort protein LMBD1 (Q9NUN5). Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors.

This gene encodes a lysosomal membrane protein that may be involved in the transport and metabolism of cobalamin. This protein also interacts with the large form of the hepatitis delta antigen and may be required for the nucleocytoplasmic shuttling of the hepatitis delta virus. Mutations in this gene are associated with the vitamin B12 metabolism disorder termed, homocystinuria-megaloblastic anemia complementation type F.

Source: NCBI Gene 55788 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylmalonic aciduria and homocystinuria type cblF (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 558 total — 27 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 58
• MANE Select transcript: NM_018368

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23038
Approved symbol	LMBRD1
Name	LMBR1 domain containing 1
Location	6q13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11240, bA810I22.1, cblF
Ensembl gene	ENSG00000168216
Ensembl biotype	protein_coding
OMIM	612625
Entrez	55788

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 21 protein_coding, 12 nonsense_mediated_decay, 7 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000370570, ENST00000472827, ENST00000647650, ENST00000647655, ENST00000647669, ENST00000647934, ENST00000647964, ENST00000648168, ENST00000648210, ENST00000648265, ENST00000648303, ENST00000648330, ENST00000648394, ENST00000648635, ENST00000648743, ENST00000649011, ENST00000649028, ENST00000649054, ENST00000649057, ENST00000649166, ENST00000649370, ENST00000649373, ENST00000649404, ENST00000649673, ENST00000649679, ENST00000649744, ENST00000649795, ENST00000649918, ENST00000649934, ENST00000649958, ENST00000649970, ENST00000650035, ENST00000650043, ENST00000650107, ENST00000650124, ENST00000650473, ENST00000651675, ENST00000875437, ENST00000875438, ENST00000875439, ENST00000875440, ENST00000875441, ENST00000934477

RefSeq mRNA: 4 — MANE Select: NM_018368 NM_001363722, NM_001367271, NM_001367272, NM_018368

CCDS: CCDS4969, CCDS87415

Canonical transcript exons

ENST00000649934 — 16 exons

Exon	Start	End
ENSE00001203660	69700765	69700869
ENSE00001912578	69674010	69676271
ENSE00002140758	69701889	69701953
ENSE00002141659	69790296	69790472
ENSE00002144883	69701443	69701545
ENSE00002148099	69780494	69780554
ENSE00002156089	69718956	69719081
ENSE00002158241	69737942	69738015
ENSE00002172134	69713645	69713797
ENSE00002176166	69752259	69752356
ENSE00002179597	69749341	69749408
ENSE00002186544	69741789	69741877
ENSE00003559552	69699043	69699192
ENSE00003564458	69676450	69676541
ENSE00003608605	69697563	69697641
ENSE00003839518	69796813	69797010

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.6584 / max 542.7415, expressed in 1814 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74302	17.2538	1714
74303	15.6419	1751
74306	0.8617	566
204047	0.6744	344
74300	0.6068	288
74305	0.4067	192
74299	0.2933	131
74307	0.2799	142
74301	0.2735	142
74304	0.1616	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.80	gold quality
oocyte	CL:0000023	98.66	gold quality
pigmented layer of retina	UBERON:0001782	98.27	gold quality
islet of Langerhans	UBERON:0000006	98.23	gold quality
olfactory bulb	UBERON:0002264	98.18	gold quality
bronchial epithelial cell	CL:0002328	98.04	gold quality
corpus callosum	UBERON:0002336	97.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.75	gold quality
choroid plexus epithelium	UBERON:0003911	97.70	gold quality
spinal cord	UBERON:0002240	97.67	gold quality
upper leg skin	UBERON:0004262	97.66	gold quality
cerebellar vermis	UBERON:0004720	97.60	gold quality
calcaneal tendon	UBERON:0003701	97.57	gold quality
jejunal mucosa	UBERON:0000399	97.46	gold quality
epithelium of bronchus	UBERON:0002031	97.21	gold quality
bronchus	UBERON:0002185	97.00	gold quality
postcentral gyrus	UBERON:0002581	96.91	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.91	gold quality
ileal mucosa	UBERON:0000331	96.87	gold quality
skin of hip	UBERON:0001554	96.81	gold quality
adult organism	UBERON:0007023	96.65	gold quality
cranial nerve II	UBERON:0000941	96.64	gold quality
type B pancreatic cell	CL:0000169	96.60	gold quality
corpus epididymis	UBERON:0004359	96.56	gold quality
adrenal tissue	UBERON:0018303	96.55	gold quality
seminal vesicle	UBERON:0000998	96.53	gold quality
pancreas	UBERON:0001264	96.52	gold quality
colonic mucosa	UBERON:0000317	96.50	gold quality
gall bladder	UBERON:0002110	96.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.46	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting LMBRD1, 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-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309

Literature-anchored findings (GeneRIF, showing 9)

• LMBRD1 is the gene underlying the cblF defect of cobalamin metabolism and suggests that LMBD1 is a lysosomal membrane exporter for cobalamin. (PMID:19136951)
• a LMBRD1 mutation causes the cblF defect of vitamin B(12) metabolism in a Turkish patient [case report] (PMID:20127417)
• LMBRD1: the gene for the cblF defect of vitamin B metabolism. (PMID:20446115)
• novel mutations in LMBRD1 in three patients (PMID:21303734)
• These data indicate that by forming complexes with lamin A/C and nucleoporins, NESI facilitates the CRM1-independent nuclear export of large hepatitis delta antigen. (PMID:23175358)
• LMBD1 plays an imperative role in mediating and regulating the endocytosis of the IR. (PMID:24078630)
• Results propose a model whereby membrane-bound LMBD1 and ABCD4 facilitate the vectorial delivery of lysosomal vitamin B12 to cytoplasmic MMACHC. (PMID:25535791)
• endogenous ABCD4 was localized to both lysosomes and the ER, and its lysosomal localization was disturbed by knockout of LMBRD1 (PMID:27456980)
• Data suggest that ABCD4 lysosomal targeting depends on co-expression of and interaction with LMBRD1; mutations in LMBRD1 and ABCD4 that result in cobalamin metabolism disorders cblF and cblJ (or mutations in ATPase domain) disrupt interactions between LMBRD1 and ABCD4. (LMBRD1 = nuclear export signal-interacting protein; ABCD4 = ATP-binding cassette, sub-family D (ALD), member 4) (PMID:28572511)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lmbrd1	ENSDARG00000104223
mus_musculus	Lmbrd1	ENSMUSG00000073725
rattus_norvegicus	Lmbrd1	ENSRNOG00000012178

Protein

Protein identifiers

Lysosomal cobalamin transport escort protein LMBD1 — Q9NUN5 (reviewed: Q9NUN5)

Alternative names: HDAg-L-interacting protein NESI, LMBR1 domain-containing protein 1, Nuclear export signal-interacting protein

All UniProt accessions (16): A0A3B3IRL1, A0A3B3IRN0, A0A3B3IRS7, A0A3B3IS10, A0A3B3IS99, A0A3B3IT31, A0A3B3IT65, A0A3B3ITM4, A0A3B3ITP2, A0A3B3ITR7, A0A3B3IU68, A0A3B3IU91, A0A3B3IU99, A0A3F2YP66, A0A494C126, Q9NUN5

UniProt curated annotations — full annotation on UniProt →

Function. Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors. Targets ABCD4 transporter from the endoplasmic reticulum to the lysosome. Then forms a complex with lysosomal ABCD4 and cytoplasmic MMACHC to transport cobalamin across the lysosomal membrane. Acts as an adapter protein which plays an important role in mediating and regulating the internalization of the insulin receptor (INSR). Involved in clathrin-mediated endocytosis of INSR via its interaction with adapter protein complex 2. Essential for the initiation of gastrulation and early formation of mesoderm structures during embryogenesis. (Microbial infection) May play a role in the assembly of hepatitis delta virus (HDV).

Subunit / interactions. (Microbial infection) Interacts with hepatitis delta virus NES (HDAg-L). Interacts with ABCD4; this interaction induces the translocation of ABCD4 from the endoplasmic reticulum to the lysosome. Interacts with ABCD4 and MMACHC; this interaction ensures the transport of cobalamin from the lysosome to the cytoplasm. Interacts with INSR, adapter protein complex 2 and clathrin heavy chain.

Subcellular location. Endoplasmic reticulum membrane. Lysosome membrane. Cell membrane. Cytoplasmic vesicle. Clathrin-coated vesicle.

Tissue specificity. Isoform 3 is expressed in liver.

Post-translational modifications. N-glycosylated.

Disease relevance. Methylmalonic aciduria and homocystinuria, cblF type (MAHCF) [MIM:277380] An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). It is due to accumulation of free cobalamin in lysosomes, thus hindering its conversion to cofactors. Clinical features include developmental delay, stomatitis, glossitis, seizures and methylmalonic aciduria responsive to vitamin B12. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the LIMR family. LMBRD1 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NUN5-1	1	yes
Q9NUN5-2	2
Q9NUN5-3	3, NESI
Q9NUN5-4	4

RefSeq proteins (4): NP_001350651, NP_001354200, NP_001354201, NP_060838* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006876	LMBR1-like_membr_prot	Family
IPR050854	LMBD1_LysCbl_Transport	Family

Pfam: PF04791

UniProt features (42 total): topological domain 10, transmembrane region 9, glycosylation site 6, splice variant 4, mutagenesis site 4, modified residue 3, sequence variant 3, short sequence motif 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NUN5-F1	84.17	0.41

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 (3): 238, 528, 531

Glycosylation sites (6): 78, 88, 170, 347, 448, 457

Mutagenesis-validated functional residues (4):

Position	Phenotype
78	does not affect glycosylation status; when associated with q-88.
88	does not affect glycosylation status; when associated with q-78.
448	affects glycosylation status; when associated with q-457.
457	affects glycosylation status. affects glycosylation status; when associated with q-448.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-5683329	Defective ABCD4 causes MAHCJ
R-HSA-9758881	Uptake of dietary cobalamins into enterocytes
R-HSA-9758890	Transport of RCbl within the body
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-3296469	Defects in cobalamin (B12) metabolism
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-5619084	ABC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters
R-HSA-5668914	Diseases of metabolism

MSigDB gene sets: 0 (showing top):

GO Biological Process (5): gastrulation (GO:0007369), insulin receptor internalization (GO:0038016), protein localization to lysosome (GO:0061462), clathrin-dependent endocytosis (GO:0072583), endocytosis (GO:0006897)

GO Molecular Function (6): insulin receptor binding (GO:0005158), cobalamin binding (GO:0031419), clathrin heavy chain binding (GO:0032050), AP-2 adaptor complex binding (GO:0035612), protein transporter activity (GO:0140318), protein binding (GO:0005515)

GO Cellular Component (9): lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), clathrin-coated endocytic vesicle (GO:0045334), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Cobalamin (Cbl, vitamin B12) transport and metabolism	2
Disease	2
Defects in cobalamin (B12) metabolism	1
ABC transporter disorders	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1
Defects in vitamin and cofactor metabolism	1
Diseases of metabolism	1
Disorders of transmembrane transporters	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
receptor internalization	1
protein localization to vacuole	1
receptor-mediated endocytosis	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
signaling receptor binding	1
vitamin binding	1
tetrapyrrole binding	1
heterocyclic compound binding	1
clathrin binding	1
protein-containing complex binding	1
transporter activity	1
binding	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
coated vesicle	1
clathrin-coated vesicle	1
endocytic vesicle	1
lytic vacuole	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular vesicle	1

Protein interactions and networks

STRING

572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LMBRD1	MMADHC	Q9H3L0	989
LMBRD1	MMAA	Q8IVH4	975
LMBRD1	MMACHC	Q9Y4U1	972
LMBRD1	MMAB	Q96EY8	955
LMBRD1	MTR	Q99707	950
LMBRD1	MTRR	Q9UBK8	944
LMBRD1	MMUT	P22033	931
LMBRD1	CD320	Q9NPF0	886
LMBRD1	TCN2	P20062	825
LMBRD1	ABCD4	O14678	812
LMBRD1	MTHFR	P42898	687
LMBRD1	H7C2H4	H7C2H4	677
LMBRD1	CBL	P22681	663
LMBRD1	P0DN79	P0DN79	646
LMBRD1	TCN1	P20061	593

IntAct

13 interactions, top by confidence:

A	B	Type	Score
LMBRD1	ABCD4	psi-mi:“MI:2364”(proximity)	0.670
ABCD4	LMBRD1	psi-mi:“MI:0403”(colocalization)	0.670
ABCD4	LMBRD1	psi-mi:“MI:0915”(physical association)	0.670
LMBRD1	RPN1	psi-mi:“MI:0915”(physical association)	0.400
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
STX12	SCAMP1	psi-mi:“MI:0914”(association)	0.350
VAMP3	SCAMP1	psi-mi:“MI:0914”(association)	0.350
LMBRD1	yegQ	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): LMBRD1 (Affinity Capture-MS), MBOAT7 (Affinity Capture-MS), LMBRD1 (Two-hybrid), LMBRD1 (Proximity Label-MS), LMBRD1 (Affinity Capture-MS), LMBRD1 (Affinity Capture-MS), LMBRD1 (Affinity Capture-MS), SLC26A7 (Cross-Linking-MS (XL-MS)), LMBRD1 (Cross-Linking-MS (XL-MS)), OTUB2 (Cross-Linking-MS (XL-MS)), RABL3 (Cross-Linking-MS (XL-MS)), VTI1B (Cross-Linking-MS (XL-MS)), LMBRD1 (Cross-Linking-MS (XL-MS)), LMBRD1 (Cross-Linking-MS (XL-MS)), LMBRD1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2AF53, A4FV75, A4K2N5, A4K2W1, A5A6S6, A6QL84, A6ZIQ8, A9JRA0, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O60337, P58749, Q08DE2, Q108U3, Q2TBU2, Q3SYY9, Q3TMP8, Q4R5E3, Q58DA4, Q5BJW3, Q5JZQ8, Q5R8H8, Q5R9W1, Q5RBJ7, Q5RFE0, Q5ZII3, Q62302, Q6UWH6, Q6ZQ89, Q78S06, Q7SYC7, Q7ZUA6, Q86W33, Q8CIF6, Q8K0B2, Q8N2H4, Q8NBJ9, Q8NFB2

Diamond homologs: A1C3U0, A1DB12, A2R920, A4RE85, A6QTW5, A6RN41, A7F2V9, A7RM45, B0YA61, B2AA26, B2WCU2, Q0D219, Q0UUE1, Q0VGV9, Q1E5A9, Q2HDJ0, Q2TZ20, Q3SYY9, Q4R5E3, Q4WCL2, Q5BDG8, Q5PR61, Q5ZI05, Q6AZ61, Q7SDN3, Q7SYR6, Q8K0B2, Q9NUN5, Q54KD1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	28
Uncertain significance	160
Likely benign	265
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1459108	NC_000006.11:g.(?70459213)(70462268_?)del	Pathogenic
1687319	NM_018368.4(LMBRD1):c.1094_1095del (p.Leu365fs)	Pathogenic
1963521	NC_000006.12:g.69780555del	Pathogenic
225048	NM_018368.4(LMBRD1):c.1056del (p.Asn353fs)	Pathogenic
2706238	NM_018368.4(LMBRD1):c.741_742del (p.Ile248fs)	Pathogenic
2712623	NM_018368.4(LMBRD1):c.358del (p.Tyr120fs)	Pathogenic
2726203	NM_018368.4(LMBRD1):c.376A>T (p.Lys126Ter)	Pathogenic
2734911	NM_018368.4(LMBRD1):c.848_851del (p.Glu283fs)	Pathogenic
2745402	NM_018368.4(LMBRD1):c.1172G>A (p.Trp391Ter)	Pathogenic
2748820	NM_018368.4(LMBRD1):c.528del (p.Lys176_Val177insTer)	Pathogenic
2761830	NM_018368.4(LMBRD1):c.229C>T (p.Gln77Ter)	Pathogenic
2780339	NM_018368.4(LMBRD1):c.614del (p.Met205fs)	Pathogenic
2800010	NM_018368.4(LMBRD1):c.1321C>T (p.Gln441Ter)	Pathogenic
2838155	NM_018368.4(LMBRD1):c.481_484del (p.Val161fs)	Pathogenic
2896786	NM_018368.4(LMBRD1):c.63dup (p.Leu22fs)	Pathogenic
2914710	NM_018368.4(LMBRD1):c.1443C>A (p.Tyr481Ter)	Pathogenic
2986617	NM_018368.4(LMBRD1):c.829C>T (p.Arg277Ter)	Pathogenic
3002392	NM_018368.4(LMBRD1):c.373G>T (p.Glu125Ter)	Pathogenic
3003435	NM_018368.4(LMBRD1):c.775C>T (p.Arg259Ter)	Pathogenic
3010436	NM_018368.4(LMBRD1):c.1251dup (p.Leu418fs)	Pathogenic
3016240	NM_018368.4(LMBRD1):c.317_318del (p.Ser106fs)	Pathogenic
3594091	NM_018368.4(LMBRD1):c.916-1G>T	Pathogenic
3625107	NM_018368.4(LMBRD1):c.690del (p.Ala231fs)	Pathogenic
3663395	NC_000006.12:g.69697707_69697708insTATCAGATTATCAGAAGTTATATTAGTCTGAAAGATAAAAATACAGTTAAAATATAAAAACCGCATTAATAAATACATTTGGATTTAAAAAGT	Pathogenic
4731228	NM_018368.4(LMBRD1):c.1067del (p.Leu356fs)	Pathogenic
518	NM_018368.4(LMBRD1):c.404del (p.Thr135fs)	Pathogenic
847318	NM_018368.4(LMBRD1):c.1156C>T (p.Arg386Ter)	Pathogenic
1346115	NM_018368.4(LMBRD1):c.1189-1G>A	Likely pathogenic
1471643	NM_018368.4(LMBRD1):c.562+1G>A	Likely pathogenic
1683362	NM_018368.4(LMBRD1):c.1396_1397insTC (p.Cys466fs)	Likely pathogenic

SpliceAI

2737 predictions. Top by Δscore:

Variant	Effect	Δscore
6:69676448:ACC:A	donor_gain	1.0000
6:69676449:CCC:C	donor_gain	1.0000
6:69676537:CTGAT:C	acceptor_gain	1.0000
6:69676538:TGAT:T	acceptor_gain	1.0000
6:69676540:ATC:A	acceptor_loss	1.0000
6:69676541:TC:T	acceptor_loss	1.0000
6:69676542:C:CC	acceptor_gain	1.0000
6:69676542:CTGTG:C	acceptor_loss	1.0000
6:69697557:TTTTA:T	donor_loss	1.0000
6:69697558:TTTA:T	donor_loss	1.0000
6:69697559:TTACC:T	donor_loss	1.0000
6:69697560:TA:T	donor_loss	1.0000
6:69697562:CC:C	donor_loss	1.0000
6:69697637:TTAGT:T	acceptor_gain	1.0000
6:69697638:TAGT:T	acceptor_gain	1.0000
6:69697639:AGTC:A	acceptor_loss	1.0000
6:69697640:GTC:G	acceptor_loss	1.0000
6:69697641:TCTG:T	acceptor_loss	1.0000
6:69697642:C:CC	acceptor_gain	1.0000
6:69697642:CTG:C	acceptor_loss	1.0000
6:69697643:T:G	acceptor_loss	1.0000
6:69699038:CTTA:C	donor_loss	1.0000
6:69699039:TTA:T	donor_loss	1.0000
6:69699040:TACCT:T	donor_loss	1.0000
6:69699042:CCT:C	donor_gain	1.0000
6:69699188:TATAA:T	acceptor_gain	1.0000
6:69699189:ATAA:A	acceptor_gain	1.0000
6:69699190:TAA:T	acceptor_gain	1.0000
6:69699191:AA:A	acceptor_gain	1.0000
6:69699193:C:CA	acceptor_loss	1.0000

AlphaMissense

3537 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:69676535:C:G	C475S	1.000
6:69676536:A:T	C475S	1.000
6:69780549:C:A	W84C	1.000
6:69780549:C:G	W84C	1.000
6:69676534:A:C	C475W	0.999
6:69676536:A:G	C475R	0.999
6:69697582:A:C	C466W	0.999
6:69697583:C:G	C466S	0.999
6:69697583:C:T	C466Y	0.999
6:69697584:A:G	C466R	0.999
6:69697584:A:T	C466S	0.999
6:69699065:C:T	G439E	0.999
6:69737967:C:T	G204E	0.999
6:69737968:C:G	G204R	0.999
6:69737968:C:T	G204R	0.999
6:69790342:T:A	D67V	0.999
6:69790342:T:G	D67A	0.999
6:69790343:C:A	D67Y	0.999
6:69790343:C:G	D67H	0.999
6:69676464:A:G	W499R	0.998
6:69676464:A:T	W499R	0.998
6:69676535:C:A	C475F	0.998
6:69676535:C:T	C475Y	0.998
6:69697583:C:A	C466F	0.998
6:69699058:T:A	Q441H	0.998
6:69699058:T:G	Q441H	0.998
6:69699065:C:A	G439V	0.998
6:69699077:T:C	Y435C	0.998
6:69700784:A:T	I390K	0.998
6:69700856:T:A	D366V	0.998

dbSNP variants (sampled 300 via entrez): RS1000056478 (6:69752918 A>G), RS1000070039 (6:69696241 T>A), RS1000107281 (6:69797572 T>C), RS1000108069 (6:69752929 T>C), RS1000113264 (6:69704020 A>G), RS1000120203 (6:69798039 A>G), RS1000128278 (6:69753175 A>T), RS1000128952 (6:69700947 T>G), RS1000151546 (6:69710481 T>C), RS1000177362 (6:69791429 G>A), RS1000177849 (6:69784048 G>T), RS1000206437 (6:69704350 GA>G), RS1000206941 (6:69746766 T>A), RS1000226083 (6:69766050 T>C), RS1000245086 (6:69759461 A>C)

Disease associations

OMIM: gene MIM:612625 | disease phenotypes: MIM:277380, MIM:277400, MIM:222448

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonic aciduria and homocystinuria type cblF	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
methylmalonic aciduria and homocystinuria type cblF	Definitive	AR

Mondo (3): methylmalonic aciduria and homocystinuria type cblF (MONDO:0010183), methylmalonic aciduria and homocystinuria type cblC (MONDO:0010184), Donnai-Barrow syndrome (MONDO:0009104)

Orphanet (4): Methylmalonic acidemia with homocystinuria type cblF (Orphanet:79284), Methylmalonic acidemia with homocystinuria (Orphanet:26), Methylmalonic acidemia with homocystinuria, type cblC (Orphanet:79282), Donnai-Barrow syndrome (Orphanet:2143)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000122	Unilateral renal agenesis
HP:0000175	Cleft palate
HP:0000206	Glossitis
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000286	Epicanthus
HP:0000369	Low-set ears
HP:0000988	Skin rash
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001627	Abnormal heart morphology
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001651	Dextrocardia
HP:0001762	Talipes equinovarus
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001889	Megaloblastic anemia
HP:0001903	Anemia
HP:0001999	Abnormal facial shape

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000635_7	Response to statin therapy	4.000000e-06
GCST002711_6	Sleep duration	3.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C536390	Donnai-Barrow syndrome (supp.)
C564747	Methylmalonic Aciduria and Homocystinuria, CblF Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases expression	2
perfluorooctane sulfonic acid	increases expression	2
Vehicle Emissions	decreases expression, increases abundance, increases methylation	2
Benzo(a)pyrene	affects methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
aristolochic acid I	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Atrazine	increases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Ozone	affects expression, increases abundance	1

Cellosaurus cell lines

19 cell lines: 12 finite cell line, 5 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3UM	WG3365	Finite cell line	Male
CVCL_B4F0	WG3377	Finite cell line	Male
CVCL_B4GQ	PV014	Transformed cell line	Male
CVCL_B4GR	WG3265	Finite cell line	Male
CVCL_B4GS	WG1908	Finite cell line	Female
CVCL_B4GT	WG2432	Finite cell line	Female
CVCL_B4GU	WG1087	Finite cell line	Female
CVCL_B4GV	WG1173	Finite cell line	Female
CVCL_B4GW	WG1903	Finite cell line	Male
CVCL_B4GX	WG1350	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01509287	Not specified	COMPLETED	Metabolic Screening in Patients With Donnai-Barrow Syndrome