BMPER

Summary

BMPER (BMP binding endothelial regulator, HGNC:24154) is a protein-coding gene on chromosome 7p14.3, encoding BMP-binding endothelial regulator protein (Q8N8U9). Inhibitor of bone morphogenetic protein (BMP) function, it may regulate BMP responsiveness of osteoblasts and chondrocytes.

This gene encodes a secreted protein that interacts with, and inhibits bone morphogenetic protein (BMP) function. It has been shown to inhibit BMP2- and BMP4-dependent osteoblast differentiation and BMP-dependent differentiation of the chondrogenic cells. Mutations in this gene are associated with a lethal skeletal disorder, diaphanospondylodysostosis.

Source: NCBI Gene 168667 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diaphanospondylodysostosis (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 446 total — 14 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 55
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001365308

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24154
Approved symbol	BMPER
Name	BMP binding endothelial regulator
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Aliases	Cv2, CRIM3
Ensembl gene	ENSG00000164619
Ensembl biotype	protein_coding
OMIM	608699
Entrez	168667

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 12 nonsense_mediated_decay, 8 protein_coding, 7 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000297161, ENST00000436222, ENST00000444773, ENST00000448280, ENST00000476525, ENST00000494786, ENST00000496609, ENST00000647656, ENST00000647703, ENST00000648229, ENST00000648305, ENST00000648320, ENST00000648392, ENST00000648445, ENST00000648618, ENST00000648848, ENST00000648856, ENST00000648982, ENST00000649002, ENST00000649232, ENST00000649409, ENST00000649771, ENST00000649985, ENST00000650202, ENST00000650206, ENST00000650350, ENST00000650533, ENST00000650544

RefSeq mRNA: 3 — MANE Select: NM_001365308 NM_001365308, NM_001410872, NM_133468

CCDS: CCDS5442, CCDS94083

Canonical transcript exons

ENST00000649409 — 15 exons

Exon	Start	End
ENSE00001085996	34055163	34055303
ENSE00001085998	34078857	34079186
ENSE00001086005	34062002	34062047
ENSE00001086007	34058059	34058163
ENSE00001123045	33974702	33974784
ENSE00001329715	33937289	33937388
ENSE00003470092	34085756	34086092
ENSE00003498395	34051861	34051970
ENSE00003508410	33966479	33966561
ENSE00003606636	33970329	33970419
ENSE00003627101	34143230	34143360
ENSE00003644534	33906818	33906903
ENSE00003665406	34046306	34046405
ENSE00003833130	34153092	34156427
ENSE00003971901	33905539	33905746

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 81.34.

FANTOM5 (CAGE): breadth broad, TPM avg 9.0116 / max 343.0548, expressed in 857 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78085	6.5153	789
78081	0.5282	240
78084	0.4297	231
78086	0.3561	185
78090	0.2848	135
78079	0.2267	143
78083	0.1807	55
78080	0.1588	85
78082	0.1211	48
204410	0.1191	70

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper lobe of left lung	UBERON:0008952	81.34	gold quality
prefrontal cortex	UBERON:0000451	81.24	gold quality
right lung	UBERON:0002167	80.63	gold quality
cerebellar hemisphere	UBERON:0002245	80.08	gold quality
cerebellar cortex	UBERON:0002129	80.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.95	gold quality
upper lobe of lung	UBERON:0008948	79.43	gold quality
vermiform appendix	UBERON:0001154	79.03	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.66	gold quality
cerebellum	UBERON:0002037	78.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.81	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.73	gold quality
stromal cell of endometrium	CL:0002255	77.31	gold quality
secondary oocyte	CL:0000655	76.09	gold quality
colonic epithelium	UBERON:0000397	75.62	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	75.40	gold quality
endocervix	UBERON:0000458	75.25	gold quality
omental fat pad	UBERON:0010414	74.65	gold quality
anterior cingulate cortex	UBERON:0009835	74.61	gold quality
peritoneum	UBERON:0002358	74.56	gold quality
right lobe of liver	UBERON:0001114	74.11	gold quality
right frontal lobe	UBERON:0002810	73.95	gold quality
right ovary	UBERON:0002118	73.70	gold quality
frontal cortex	UBERON:0001870	73.32	gold quality
adipose tissue of abdominal region	UBERON:0007808	73.32	gold quality
body of stomach	UBERON:0001161	73.09	gold quality
gastrocnemius	UBERON:0001388	73.00	gold quality
muscle of leg	UBERON:0001383	72.96	gold quality
neocortex	UBERON:0001950	72.89	gold quality
lung	UBERON:0002048	72.82	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	604.62
E-HCAD-35	yes	62.82
E-HCAD-10	yes	34.77
E-ANND-3	yes	19.48
E-MTAB-8271	yes	8.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP4, DLX5, FOXO1, KLF15

miRNA regulators (miRDB)

104 targeting BMPER, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-205-3P	99.92	69.92	3165

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 25)

• BMPER is a novel BMP-binding protein that is expressed by endothelial cell precursors, has BMP-antagonizing activity, and may play a role in endothelial cell differentiation by modulating local BMP activity (PMID:12897139)
• Crossveinless-2 is an inhibitor of BMP function (PMID:14766204)
• BMPER is an endothelial cell regulator and controls bone morphogenetic protein-4-dependent angiogenesis. (PMID:18787191)
• BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development, while defects in BMPER produce Diaphanospondylodysostosis. (PMID:20869035)
• Diaphonospondylodysostosis is caused by loss of BMPER function. (PMID:21990102)
• The data unequivocally demonstrated that BMPER is highly expressed in malignant tumors and that the growth of lung, colon, and uterine carcinomas is dependent on the presence of BMPER. (PMID:22020334)
• Mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium. (PMID:22474252)
• Bmper is a critical regulator of Bmp-mediated vascular inflammation and that the fine-tuning of Bmp and Bmper levels is essential in the maintenance of normal vascular homeostasis. (PMID:22772758)
• BMPER is a novel regulator of the osteoblast-like differentiation of HCASMCs. (PMID:22778264)
• these results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular cell homeostasis. (PMID:23641068)
• The proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis. (PMID:25503991)
• BMPER-dependent pathway involved in high glucose induced alkaline phosphatase expression in vascular smooth muscle cells. (PMID:26264461)
• BMPER variants associated with a novel, attenuated subtype of diaphanospondylodysostosis. (PMID:26467725)
• that BMPER-modulated BMP pathway activity regulates VE-cadherin expression and vascular barrier function (PMID:27995357)
• Overexpression of BMPER remarkably enhanced BMP-2-induced osteogenic differentiation, while suppression of BMPER effectively inhibited this process both in vitro and in vivo. (PMID:29518774)
• A novel homozygous mutation in BMPER (c.410T>A; p.Val137Asp) was found in three fetuses with diaphanospondylodysostosis. (PMID:30006055)
• Internal cleavage and synergy with TWSG1 enhance BMP-4 inhibition by BMPER. (PMID:30125619)
• BMPER possesses valuable discriminative capacity for urosepsis and is a strong predictor of adverse outcome in patients with urosepsis. (PMID:30800678)
• Overexpression of BMPER in Ovarian Cancer and the Mechanism by which It Promotes Malignant Biological Behavior in Tumor Cells. (PMID:32309430)
• Integrated In Silico-In Vitro Identification and Optimization of Bone Morphogenic Protein-2 Armpit Epitope as Its Antagonist Binding Site. (PMID:33130958)
• Expansion of the mutational spectrum of BMPER leading to diaphanospondylodysostosis and description of the associated disease process. (PMID:34288564)
• BMPER alleviates ischemic brain injury by protecting neurons and inhibiting neuroinflammation via Smad3-Akt-Nrf2 pathway. (PMID:34904361)
• Further evidence for attenuated phenotype with variants in the BMPER gene causing DSD: Case report and literature review. (PMID:35240322)
• IL-6/Stat3 suppresses osteogenic differentiation in ossification of the posterior longitudinal ligament via miR-135b-mediated BMPER reduction. (PMID:36305971)
• BMPER is a marker of adipose progenitors and adipocytes and a positive modulator of adipogenesis. (PMID:37311809)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	bmper	ENSDARG00000101980
mus_musculus	Bmper	ENSMUSG00000031963
rattus_norvegicus	Bmper	ENSRNOG00000015357

Paralogs (19): CHRDL2 (ENSG00000054938), CHRD (ENSG00000090539), CHRDL1 (ENSG00000101938), TECTA (ENSG00000109927), VWF (ENSG00000110799), MUC5B (ENSG00000117983), KCP (ENSG00000135253), ZAN (ENSG00000146839), CRIM1 (ENSG00000150938), OTOGL (ENSG00000165899), VWCE (ENSG00000167992), VWC2L (ENSG00000174453), MUC6 (ENSG00000184956), OTOG (ENSG00000188162), VWC2 (ENSG00000188730), MUC2 (ENSG00000198788), MUC19 (ENSG00000205592), MUC5AC (ENSG00000215182), FCGBP (ENSG00000275395)

Protein

Protein identifiers

BMP-binding endothelial regulator protein — Q8N8U9 (reviewed: Q8N8U9)

Alternative names: Bone morphogenetic protein-binding endothelial cell precursor-derived regulator, Protein crossveinless-2

All UniProt accessions (19): A0A090N7U6, A0A3B3IRM9, A0A3B3IRP7, A0A3B3IRQ4, A0A3B3IS51, A0A3B3ISK6, Q8N8U9, A0A3B3ISL7, A0A3B3ISN0, A0A3B3IT71, A0A3B3ITB6, A0A3B3ITD3, A0A3B3ITU0, A0A3B3ITW7, A0A3B3ITX1, A0A3B3ITY4, A0A3B3ITZ8, A0A3B3IUC5, A0A3B3IUD9

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of bone morphogenetic protein (BMP) function, it may regulate BMP responsiveness of osteoblasts and chondrocytes.

Subunit / interactions. Interacts with BMP4.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in lung, and brain and also in primary chondrocytes.

Disease relevance. Diaphanospondylodysostosis (DSD) [MIM:608022] A rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics of the phenotype include a small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, a depressed nasal bridge with a short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (3): NP_001352237, NP_001397801, NP_597725 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001007	VWF_dom	Domain
IPR001846	VWF_type-D	Domain
IPR002919	TIL_dom	Domain
IPR014853	VWF/SSPO/ZAN-like_Cys-rich_dom	Domain
IPR036084	Ser_inhib-like_sf	Homologous_superfamily
IPR052424	Kielin_Chordin-BMP_Reg	Family

Pfam: PF00093, PF00094, PF01826, PF08742

UniProt features (19 total): domain 7, glycosylation site 5, disulfide bond 2, sequence variant 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N8U9-F1	80.24	0.33

Functional residue map

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

Disulfide bonds (2): 364–497, 386–534

Glycosylation sites (5): 247, 255, 318, 441, 116

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 282 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, TATTATA_MIR374, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EAR_DEVELOPMENT, GOBP_SPROUTING_ANGIOGENESIS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT

GO Biological Process (17): blood vessel development (GO:0001568), ureteric bud development (GO:0001657), blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:0002043), regulation of endothelial cell migration (GO:0010594), BMP signaling pathway (GO:0030509), negative regulation of BMP signaling pathway (GO:0030514), regulation of protein localization (GO:0032880), endothelial cell activation (GO:0042118), regulation of angiogenesis (GO:0045765), inner ear development (GO:0048839), positive regulation of SMAD protein signal transduction (GO:0060391), SMAD protein signal transduction (GO:0060395), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of sprouting angiogenesis (GO:1903672), tube development (GO:0035295), system development (GO:0048731), regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090092)

GO Molecular Function (2): extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
sprouting angiogenesis	2
cell surface receptor protein serine/threonine kinase signaling pathway	2
multicellular organism development	2
vasculature development	1
mesonephric tubule development	1
endothelial cell proliferation	1
regulation of cell migration	1
endothelial cell migration	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
intracellular protein localization	1
regulation of localization	1
cell activation	1
angiogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of vasculature development	1
ear development	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of intracellular signal transduction	1
intracellular signaling cassette	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
positive regulation of angiogenesis	1
regulation of sprouting angiogenesis	1
regulation of signal transduction	1
structural molecule activity	1
extracellular matrix	1
binding	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BMPER	BMP4	P12644	913
BMPER	BMP6	P22004	910
BMPER	BMP2	P12643	876
BMPER	BMP7	P18075	814
BMPER	CHRD	Q9H2X0	773
BMPER	TWSG1	Q9GZX9	753
BMPER	INHBA	P08476	712
BMPER	BMPR2	Q13873	662
BMPER	ACVR2B	Q13705	661
BMPER	SMAD5	Q99717	654
BMPER	BMPR1A	P36894	650
BMPER	RALA	P11233	591
BMPER	GDF5	P43026	581
BMPER	FST	P19883	541
BMPER	NOG	Q13253	532
BMPER	GDF2	Q9UK05	532

IntAct

4 interactions, top by confidence:

A	B	Type	Score
BMPER	GAMMAHV.ORF31	psi-mi:“MI:0915”(physical association)	0.370
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): BMPER (Affinity Capture-MS), BMPER (Proximity Label-MS)

ESM2 similar proteins: A0A292G9J6, A0A8M9PFP2, A1L2K1, A2A863, A7E2Z9, B0S5G3, B5MFE9, F1R520, F7A4A7, F8VQ03, O93449, O94985, P16144, P35447, P53813, P98089, Q08761, Q0V9V5, Q0VCN6, Q28483, Q3ZCN5, Q5R9Q9, Q5RCW9, Q5RD64, Q61592, Q63772, Q64632, Q6DDW2, Q6DFV8, Q6PZE0, Q6Q0N0, Q8BH34, Q8BJD1, Q8CFM6, Q8CIZ8, Q8CJ69, Q8K410, Q8N2E2, Q8N8U9, Q8R553

Diamond homologs: A1Z877, B5DFC9, H9JIQ1, O08523, O75443, O88322, P02845, P07911, P10493, P19218, P25291, P27590, P34501, P41950, P48733, P55259, Q0KHY3, Q14112, Q28833, Q3U492, Q5R5C1, Q5ZQU0, Q6ZWJ8, Q70E20, Q862Z3, Q8CJ69, Q8N8U9, Q8TER0, Q91X17, Q9D733, Q9IBG7, Q9Y6R7, Q9YH85, A5A6L1, D3Z5L9, O00622, O18739, O19113, O54775, O76076

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	7
Uncertain significance	212
Likely benign	127
Benign	57

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1409421	NM_001365308.1(BMPER):c.1259C>A (p.Ser420Ter)	Pathogenic
2086264	NM_001365308.1(BMPER):c.674T>A (p.Leu225Ter)	Pathogenic
2693069	NM_001365308.1(BMPER):c.655C>T (p.Gln219Ter)	Pathogenic
30742	NM_001365308.1(BMPER):c.925C>T (p.Gln309Ter)	Pathogenic
30743	NM_001365308.1(BMPER):c.26_35delinsAGACCAGAGCGGCG (p.Ala9fs)	Pathogenic
30744	NM_001365308.1(BMPER):c.1078+5G>A	Pathogenic
30745	NM_001365308.1(BMPER):c.1109C>T (p.Pro370Leu)	Pathogenic
30746	NM_001365308.1(BMPER):c.1638T>A (p.Cys546Ter)	Pathogenic
3239384	NM_001365308.1(BMPER):c.1648_1649del (p.Val550fs)	Pathogenic
3245932	NC_000007.13:g.(?34009921)(34010051_?)del	Pathogenic
632002	NM_001365308.1(BMPER):c.816C>A (p.Cys272Ter)	Pathogenic
987346	NM_001365308.1(BMPER):c.1577G>A (p.Trp526Ter)	Pathogenic
988319	NM_001365308.1(BMPER):c.501_502del (p.Val167_Phe168insTer)	Pathogenic
988512	NM_001365308.1(BMPER):c.942G>A (p.Trp314Ter)	Pathogenic
2437599	NM_001365308.1(BMPER):c.721C>T (p.Arg241Ter)	Likely pathogenic
3245935	NC_000007.13:g.(?34006071)(34014416_?)dup	Likely pathogenic
3594596	NM_001365308.1(BMPER):c.403-2A>C	Likely pathogenic
3594597	NM_001365308.1(BMPER):c.1075G>T (p.Glu359Ter)	Likely pathogenic
3765626	NM_001365308.1(BMPER):c.531_535dup (p.Phe179fs)	Likely pathogenic
3899250	NM_001365308.1(BMPER):c.219+1G>C	Likely pathogenic
988511	NM_001365308.1(BMPER):c.416C>G (p.Thr139Arg)	Likely pathogenic

SpliceAI

3739 predictions. Top by Δscore:

Variant	Effect	Δscore
7:33906812:TTTCA:T	acceptor_loss	1.0000
7:33906813:TTCA:T	acceptor_loss	1.0000
7:33906814:TCA:T	acceptor_loss	1.0000
7:33906815:CAGGT:C	acceptor_loss	1.0000
7:33906817:G:A	acceptor_loss	1.0000
7:34051969:GG:G	donor_gain	1.0000
7:34051970:GG:G	donor_gain	1.0000
7:34055152:T:A	acceptor_gain	1.0000
7:34055153:G:A	acceptor_gain	1.0000
7:34055159:CCAG:C	acceptor_loss	1.0000
7:34055160:CAGG:C	acceptor_loss	1.0000
7:34055161:A:AG	acceptor_gain	1.0000
7:34055161:A:T	acceptor_loss	1.0000
7:34055161:AG:A	acceptor_gain	1.0000
7:34055162:G:GT	acceptor_gain	1.0000
7:34055162:GG:G	acceptor_gain	1.0000
7:34055162:GGACT:G	acceptor_gain	1.0000
7:34055301:CAGGT:C	donor_loss	1.0000
7:34055302:AGGTA:A	donor_loss	1.0000
7:34055303:GG:G	donor_loss	1.0000
7:34055304:G:GA	donor_loss	1.0000
7:34062048:G:GG	donor_gain	1.0000
7:34085753:TAG:T	acceptor_loss	1.0000
7:34085754:A:AG	acceptor_gain	1.0000
7:34085754:A:T	acceptor_loss	1.0000
7:34085754:AG:A	acceptor_gain	1.0000
7:34085755:G:GT	acceptor_gain	1.0000
7:34085755:GG:G	acceptor_gain	1.0000
7:34085755:GGT:G	acceptor_gain	1.0000
7:34085755:GGTT:G	acceptor_gain	1.0000

AlphaMissense

4524 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:34078868:T:C	C364R	1.000
7:34078869:G:A	C364Y	1.000
7:34078870:C:G	C364W	1.000
7:34085770:T:A	W475R	1.000
7:34085770:T:C	W475R	1.000
7:34085772:G:C	W475C	1.000
7:34085772:G:T	W475C	1.000
7:34143235:G:A	C584Y	1.000
7:33906892:T:A	C70S	0.999
7:33906892:T:C	C70R	0.999
7:33906893:G:C	C70S	0.999
7:33937304:T:A	C79S	0.999
7:33937305:G:C	C79S	0.999
7:34078868:T:A	C364S	0.999
7:34078869:G:C	C364S	0.999
7:34078869:G:T	C364F	0.999
7:34078881:G:A	G368E	0.999
7:34078889:C:G	H371D	0.999
7:34078892:T:G	Y372D	0.999
7:34078902:T:G	F375C	0.999
7:34078904:G:C	D376H	0.999
7:34078905:A:C	D376A	0.999
7:34078905:A:T	D376V	0.999
7:34078941:A:G	Y388C	0.999
7:34079029:G:C	W417C	0.999
7:34079029:G:T	W417C	0.999
7:34085765:T:A	I473K	0.999
7:34085830:G:C	G495R	0.999
7:34085831:G:A	G495D	0.999
7:34085836:T:C	C497R	0.999

dbSNP variants (sampled 300 via entrez): RS1000039477 (7:34107252 A>G), RS1000049593 (7:34145991 C>T), RS1000056993 (7:34132770 A>G,T), RS1000061598 (7:34018285 C>T), RS1000062675 (7:34104424 G>A,T), RS1000104305 (7:33973183 T>C,G), RS1000118626 (7:33936669 T>C), RS1000118969 (7:33995885 T>C,G), RS1000124786 (7:34064119 C>A), RS1000136621 (7:33922447 C>T), RS1000152207 (7:34051518 G>A), RS1000154064 (7:33905072 C>G,T), RS1000160960 (7:34136579 T>C), RS1000161344 (7:34038009 C>T), RS1000175329 (7:33918293 G>T)

Disease associations

OMIM: gene MIM:608699 | disease phenotypes: MIM:608022

GenCC curated gene-disease

Disease	Classification	Inheritance
diaphanospondylodysostosis	Definitive	Autosomal recessive
ischio-vertebral syndrome	Supportive	Autosomal recessive

Mondo (2): diaphanospondylodysostosis (MONDO:0011946), ischio-vertebral syndrome (MONDO:0019413)

Orphanet (1): Diaphanospondylodysostosis (Orphanet:66637)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000085	Horseshoe kidney
HP:0000105	Enlarged kidney
HP:0000175	Cleft palate
HP:0000239	Large fontanelles
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000457	Depressed nasal ridge
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000800	Cystic renal dysplasia
HP:0000921	Missing ribs
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001511	Intrauterine growth retardation
HP:0001538	Protuberant abdomen
HP:0001562	Oligohydramnios
HP:0001591	Bell-shaped thorax
HP:0001762	Talipes equinovarus
HP:0001765	Hammertoe
HP:0001804	Hypoplastic fingernail
HP:0002089	Pulmonary hypoplasia
HP:0002093	Respiratory insufficiency
HP:0002098	Respiratory distress
HP:0002126	Polymicrogyria
HP:0002475	Myelomeningocele

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002429_2	Alzheimer’s disease	1.000000e-07
GCST003262_532	Post bronchodilator FEV1	8.000000e-07
GCST004361_12	Estrone/androstenedione ratio in resected early stage-receptor positive breast cancer	7.000000e-06
GCST005212_25	Asthma	3.000000e-06
GCST005331_4	CSF tryptophan concentration in tuberculous meningitis	1.000000e-07
GCST005803_11	Corneal astigmatism	7.000000e-06
GCST006616_8	Uterine fibroid number (single vs multiple)	8.000000e-07
GCST012210_1	Longevity	8.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0007970	estrone measurement
EFO:0007972	androstenedione measurement
EFO:0008534	tryptophan measurement
EFO:1002040	Corneal astigmatism
EFO:0009410	uterine fibroid measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564305	Diaphanospondylodysostosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs757639	BMPER, OCRL	3	2.00	1	tenofovir

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects expression, affects cotreatment, decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases methylation, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
GSK-J4	increases expression	1
bisphenol F	affects cotreatment, increases methylation	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
terbufos	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
ferrous chloride	decreases expression	1
nickel sulfate	decreases expression	1
1-nitropyrene	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
3-nitrobenzanthrone	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
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	decreases expression	1
bisphenol S	decreases methylation	1

Clinical trials (associated diseases)

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