SPTBN4

Summary

SPTBN4 (spectrin beta, non-erythrocytic 4, HGNC:14896) is a protein-coding gene on chromosome 19q13.2, encoding Spectrin beta chain, non-erythrocytic 4 (Q9H254).

Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein localizes to the nuclear matrix, PML nuclear bodies, and cytoplasmic vesicles. A highly similar gene in the mouse is required for localization of specific membrane proteins in polarized regions of neurons. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 57731 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia, neuropathy, and deafness (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 620 total — 15 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 45
• MANE Select transcript: NM_020971

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14896
Approved symbol	SPTBN4
Name	spectrin beta, non-erythrocytic 4
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	SPTBN3, KIAA1642
Ensembl gene	ENSG00000160460
Ensembl biotype	protein_coding
OMIM	606214
Entrez	57731

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 retained_intron, 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000352632, ENST00000392023, ENST00000593816, ENST00000593932, ENST00000595535, ENST00000595690, ENST00000596411, ENST00000596900, ENST00000597389, ENST00000598249, ENST00000598775, ENST00000599926

RefSeq mRNA: 2 — MANE Select: NM_020971 NM_020971, NM_025213

CCDS: CCDS12559, CCDS42569

Canonical transcript exons

ENST00000598249 — 36 exons

Exon	Start	End
ENSE00002215152	40503830	40504132
ENSE00002231022	40502775	40502933
ENSE00002237488	40494897	40494977
ENSE00002243121	40512606	40513554
ENSE00002255356	40492963	40493054
ENSE00002256628	40490075	40490248
ENSE00002269880	40506236	40506386
ENSE00002270550	40472607	40472790
ENSE00002282542	40502390	40502507
ENSE00002289278	40523437	40523639
ENSE00002297078	40515311	40515448
ENSE00002300267	40487697	40487848
ENSE00002306116	40519401	40520151
ENSE00002306479	40497489	40497604
ENSE00003035903	40575411	40576464
ENSE00003473480	40556084	40556288
ENSE00003477121	40565661	40565745
ENSE00003484257	40534080	40534343
ENSE00003488497	40567663	40568282
ENSE00003492704	40554147	40554425
ENSE00003502148	40566163	40566359
ENSE00003520685	40549189	40549413
ENSE00003532361	40501921	40502033
ENSE00003548389	40554516	40554646
ENSE00003575412	40502128	40502315
ENSE00003576464	40572338	40572380
ENSE00003599133	40550238	40550327
ENSE00003616187	40560159	40560403
ENSE00003624411	40569657	40569726
ENSE00003646810	40565423	40565561
ENSE00003652791	40572019	40572192
ENSE00003664088	40557023	40557403
ENSE00003671072	40570436	40570728
ENSE00003680352	40532625	40532771
ENSE00003686326	40529041	40529131
ENSE00003846445	40467001	40467305

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 98.96.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7167 / max 246.3912, expressed in 323 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175846	1.0353	171
175844	0.5906	167
175847	0.5528	110
175845	0.3377	127
175848	0.2004	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.96	gold quality
cerebellar hemisphere	UBERON:0002245	98.90	gold quality
cerebellar cortex	UBERON:0002129	98.85	gold quality
cerebellum	UBERON:0002037	97.78	gold quality
right frontal lobe	UBERON:0002810	97.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.48	gold quality
anterior cingulate cortex	UBERON:0009835	95.00	gold quality
cingulate cortex	UBERON:0003027	94.99	gold quality
prefrontal cortex	UBERON:0000451	94.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.20	gold quality
nucleus accumbens	UBERON:0001882	94.19	gold quality
frontal cortex	UBERON:0001870	93.84	gold quality
neocortex	UBERON:0001950	93.45	gold quality
caudate nucleus	UBERON:0001873	92.67	gold quality
putamen	UBERON:0001874	92.33	gold quality
cerebral cortex	UBERON:0000956	92.22	gold quality
telencephalon	UBERON:0001893	91.90	gold quality
brain	UBERON:0000955	91.80	gold quality
amygdala	UBERON:0001876	91.71	gold quality
forebrain	UBERON:0001890	91.70	gold quality
pituitary gland	UBERON:0000007	91.62	gold quality
hypothalamus	UBERON:0001898	91.19	gold quality
adenohypophysis	UBERON:0002196	91.12	gold quality
cerebellar vermis	UBERON:0004720	90.45	gold quality
primary visual cortex	UBERON:0002436	90.40	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.33	gold quality
Ammon’s horn	UBERON:0001954	90.05	gold quality
CA1 field of hippocampus	UBERON:0003881	89.43	silver quality
temporal lobe	UBERON:0001871	89.39	gold quality
type B pancreatic cell	CL:0000169	89.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

104 targeting SPTBN4, 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-4481	100.00	66.42	1669
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6721-5P	99.93	68.92	2981

Literature-anchored findings (GeneRIF, showing 4)

• bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy, are reported. (PMID:29861105)
• betaIII spectrin controls the planarity of Purkinje cell dendrites by modulating perpendicular axon-dendrite interactions. (PMID:33234719)
• Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum. (PMID:33772159)
• Spectrin-Based Regulation of Cardiac Fibroblast Cell-Cell Communication. (PMID:36899883)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sptbn4b	ENSDARG00000092624
danio_rerio		ENSDARG00000111942
mus_musculus	Sptbn4	ENSMUSG00000011751
rattus_norvegicus	Sptbn4	ENSRNOG00000055371

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Spectrin beta chain, non-erythrocytic 4 — Q9H254 (reviewed: Q9H254)

Alternative names: Beta-IV spectrin, Spectrin, non-erythroid beta chain 3

All UniProt accessions (3): Q9H254, M0QZQ3, M0R1V6

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cytoplasm. Cytoskeleton. Cell cortex.

Tissue specificity. Expressed in skeletal muscle at the sarcolemma and in the muscle capillaries (at protein level). Abundantly expressed in brain and pancreatic islets.

Disease relevance. Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND) [MIM:617519] An autosomal recessive disorder characterized by congenital myopathy with hypotonia and muscle weakness manifesting after birth and progressing to generalized muscle atrophy, central deafness with absent brainstem-evoked potentials, and a combined axonal and demyelinating motor neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the spectrin family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9H254-1	1	yes
Q9H254-2	2
Q9H254-3	3
Q9H254-4	4
Q9H254-5	5

RefSeq proteins (2): NP_066022, NP_079489 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001589	Actinin_actin-bd_CS	Conserved_site
IPR001605	PH_dom-spectrin-type	Domain
IPR001715	CH_dom	Domain
IPR001849	PH_domain	Domain
IPR002017	Spectrin_repeat	Repeat
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016343	Spectrin_bsu	Family
IPR018159	Spectrin/alpha-actinin	Repeat
IPR036872	CH_dom_sf	Homologous_superfamily
IPR041681	PH_9	Domain

Pfam: PF00307, PF00435, PF15410

UniProt features (48 total): repeat 14, compositionally biased region 10, splice variant 9, region of interest 5, sequence conflict 4, domain 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H254-F1	72.50	0.09

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-373760	L1CAM interactions
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-597592	Post-translational protein modification
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-9675108	Nervous system development

MSigDB gene sets: 362 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEURON_MATURATION, GOBP_ADULT_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_GROWTH, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, GOBP_NEGATIVE_REGULATION_OF_ACTIN_FILAMENT_DEPOLYMERIZATION, GOBP_NEUROGENESIS

GO Biological Process (21): regulation of sodium ion transport (GO:0002028), axonogenesis (GO:0007409), neuromuscular junction development (GO:0007528), sensory perception of sound (GO:0007605), adult walking behavior (GO:0007628), fertilization (GO:0009566), negative regulation of heart rate (GO:0010459), vesicle-mediated transport (GO:0016192), transmission of nerve impulse (GO:0019226), central nervous system projection neuron axonogenesis (GO:0021952), actin cytoskeleton organization (GO:0030036), positive regulation of multicellular organism growth (GO:0040018), clustering of voltage-gated sodium channels (GO:0045162), neuromuscular process (GO:0050905), actin filament capping (GO:0051693), cardiac conduction (GO:0061337), protein-containing complex assembly (GO:0065003), protein localization to plasma membrane (GO:0072659), cytoskeleton organization (GO:0007010), intracellular protein localization (GO:0008104), adult behavior (GO:0030534)

GO Molecular Function (10): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), phospholipid binding (GO:0005543), phosphatase binding (GO:0019902), ankyrin binding (GO:0030506), spectrin binding (GO:0030507), actin filament binding (GO:0051015), cytoskeletal protein-membrane anchor activity (GO:0106006), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (25): cytoplasm (GO:0005737), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), spectrin (GO:0008091), intercalated disc (GO:0014704), membrane (GO:0016020), nuclear matrix (GO:0016363), PML body (GO:0016605), cell junction (GO:0030054), cortical actin cytoskeleton (GO:0030864), node of Ranvier (GO:0033268), paranode region of axon (GO:0033270), cell projection (GO:0042995), neuronal cell body (GO:0043025), axon initial segment (GO:0043194), axon hillock (GO:0043203), juxtaparanode region of axon (GO:0044224), extracellular exosome (GO:0070062), cell body fiber (GO:0070852), cytoskeleton (GO:0005856), adherens junction (GO:0005912), cell cortex (GO:0005938), axon (GO:0030424), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Axon guidance	2
L1CAM interactions	1
MAPK1/MAPK3 signaling	1
ER to Golgi Anterograde Transport	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Nervous system development	1
Post-translational protein modification	1
Signal Transduction	1
MAPK family signaling cascades	1
Metabolism of proteins	1
Asparagine N-linked glycosylation	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	11
main axon	4
cytoskeletal protein binding	3
nervous system process	2
cytoskeleton organization	2
lipid binding	2
protein-containing complex binding	2
actin cytoskeleton	2
sodium ion transport	1
regulation of metal ion transport	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
synapse organization	1
sensory perception of mechanical stimulus	1
adult locomotory behavior	1
walking behavior	1
sexual reproduction	1
reproductive process	1
regulation of heart rate	1
negative regulation of heart contraction	1
transport	1
cellular process	1
action potential	1
cell communication	1
chemical synaptic transmission	1
central nervous system neuron axonogenesis	1
actin filament-based process	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
neuronal ion channel clustering	1
negative regulation of actin filament depolymerization	1
negative regulation of actin filament polymerization	1
regulation of heart contraction	1
cellular component assembly	1
protein-containing complex organization	1
protein localization to membrane	1
protein localization to cell periphery	1

Protein interactions and networks

STRING

1578 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPTBN4	ANK3	Q12955	996
SPTBN4	NRCAM	Q92823	939
SPTBN4	ANK1	P16157	907
SPTBN4	NFASC	O94856	903
SPTBN4	ANK2	Q01484	862
SPTBN4	GLDN	Q6ZMI3	798
SPTBN4	KCNQ2	O43526	747
SPTBN4	EPB41	P11171	744
SPTBN4	SPTA1	P02549	740
SPTBN4	SPTAN1	Q13813	736
SPTBN4	KCNK2	O95069	723
SPTBN4	CNTNAP1	P78357	720
SPTBN4	SCN8A	Q9UQD0	665
SPTBN4	BCAN	Q96GW7	655
SPTBN4	AP5S1	Q9NUS5	648

IntAct

36 interactions, top by confidence:

A	B	Type	Score
HOMER1	TRAF5	psi-mi:“MI:0914”(association)	0.740
BRAF	KRAS	psi-mi:“MI:0914”(association)	0.680
RSBN1	SETD1A	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
PTPRN	SPTBN4	psi-mi:“MI:0915”(physical association)	0.510
SPTBN4	DISC1	psi-mi:“MI:0915”(physical association)	0.510
RAD51D	SPTBN4	psi-mi:“MI:0915”(physical association)	0.400
ETS1	SPTBN4	psi-mi:“MI:0915”(physical association)	0.400
PNP	SPTBN4	psi-mi:“MI:0915”(physical association)	0.400
SPTBN4	CDKL5	psi-mi:“MI:0915”(physical association)	0.370
CELSR3	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
SPTBN4	CDC37	psi-mi:“MI:0915”(physical association)	0.370
GADD45A	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
SPTBN4	GSK3B	psi-mi:“MI:0915”(physical association)	0.370
CENPU	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
SPTBN4	NEK2	psi-mi:“MI:0915”(physical association)	0.370
PFDN1	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
PTPRN2	SPTBN4	psi-mi:“MI:0915”(physical association)	0.370
MAPT	NCAN	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
PCDHGC3	FYN	psi-mi:“MI:0914”(association)	0.350
ANTXR2	HS1BP3	psi-mi:“MI:0914”(association)	0.350
A2ML1	SPTBN4	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): SPTBN4 (Affinity Capture-MS), SPTBN4 (Biochemical Activity), SPTBN4 (Affinity Capture-MS), SPTBN4 (Affinity Capture-MS), SPTBN4 (Affinity Capture-MS), SPTBN4 (Affinity Capture-MS), SPTBN4 (Two-hybrid), SPTBN4 (Affinity Capture-Western), SPTBN4 (Affinity Capture-RNA), SPTBN4 (Affinity Capture-Western), SPTBN4 (Affinity Capture-MS), ARC (Reconstituted Complex), SPTBN4 (Affinity Capture-MS), SPTBN4 (Proximity Label-MS), ANK3 (Affinity Capture-Western)

ESM2 similar proteins: A2CG49, D3ZHV2, F1M0Z1, L7UZ85, O13728, O15020, O15068, O60229, O75962, O88990, P02549, P05095, P07751, P08032, P11277, P11533, P13395, P15508, P16086, P16546, P18091, P20111, P30427, P35609, P97924, Q00963, Q01082, Q08043, Q0III9, Q0KL02, Q13813, Q15149, Q1LUA6, Q3ZC55, Q62261, Q7PKQ5, Q86VI3, Q8R307, Q90734, Q99PK0

Diamond homologs: A5D7D1, D3ZEN0, D3ZHA0, D3ZHV2, D3ZQL6, E1BBG2, F1MF74, F1RA39, F6QZ15, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O75369, O76329, O88990, O94851, O97592, P05094, P05095, P07751, P11277, P11530, P11531, P11532, P11533, P12814, P13395, P13466, P15508, P16086, P16546, P18091, P20111, P21333, P30427, P35609

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	17
Uncertain significance	408
Likely benign	96
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030745	NM_020971.3(SPTBN4):c.3589C>T (p.Gln1197Ter)	Pathogenic
1675743	NM_020971.3(SPTBN4):c.6320_6336+10del	Pathogenic
1675761	GRCh37/hg19 19q13.2(chr19:40978529-40978697)x1	Pathogenic
2572987	NM_020971.3(SPTBN4):c.6016C>T (p.Arg2006Ter)	Pathogenic
3254916	NM_020971.3(SPTBN4):c.5173C>T (p.Gln1725Ter)	Pathogenic
3390929	NM_020971.3(SPTBN4):c.2265G>A (p.Trp755Ter)	Pathogenic
375254	NM_020971.3(SPTBN4):c.1597C>T (p.Gln533Ter)	Pathogenic
521395	NM_020971.3(SPTBN4):c.2052_2071dup (p.Leu691fs)	Pathogenic
559545	NM_020971.3(SPTBN4):c.3820G>T (p.Glu1274Ter)	Pathogenic
985015	NM_020971.3(SPTBN4):c.1813C>T (p.Gln605Ter)	Pathogenic
986056	NM_020971.3(SPTBN4):c.3829del (p.Gln1277fs)	Pathogenic
987133	NM_020971.3(SPTBN4):c.5091_5092del (p.Gln1697fs)	Pathogenic
987745	NM_020971.3(SPTBN4):c.3375_3393del (p.Asp1126fs)	Pathogenic
987746	NM_020971.3(SPTBN4):c.1149dup (p.Asn384fs)	Pathogenic
988586	NM_020971.3(SPTBN4):c.1249del (p.Leu417fs)	Pathogenic
1878626	NM_020971.3(SPTBN4):c.1897del (p.Ala633fs)	Likely pathogenic
2441659	NM_020971.3(SPTBN4):c.1906C>T (p.Arg636Ter)	Likely pathogenic
2503813	NM_020971.3(SPTBN4):c.4960C>T (p.Gln1654Ter)	Likely pathogenic
2631284	NM_020971.3(SPTBN4):c.6769C>T (p.Gln2257Ter)	Likely pathogenic
3065352	NM_020971.3(SPTBN4):c.2903+2T>C	Likely pathogenic
3362455	NM_020971.3(SPTBN4):c.1217T>C (p.Leu406Pro)	Likely pathogenic
3362729	NM_020971.3(SPTBN4):c.2535_2554del (p.Gly846fs)	Likely pathogenic
3392510	NM_020971.3(SPTBN4):c.2326_2341dup (p.Asp781delinsAlaProValArgArgTer)	Likely pathogenic
3775463	NM_020971.3(SPTBN4):c.3948+1G>A	Likely pathogenic
3776278	NM_020971.3(SPTBN4):c.6826G>T (p.Glu2276Ter)	Likely pathogenic
4073460	NM_020971.3(SPTBN4):c.1795del (p.Leu599fs)	Likely pathogenic
4813047	NM_020971.3(SPTBN4):c.1090C>T (p.Gln364Ter)	Likely pathogenic
559549	NM_020971.3(SPTBN4):c.7453del (p.Ala2485fs)	Likely pathogenic
800778	NM_020971.3(SPTBN4):c.4584+1G>T	Likely pathogenic
808582	NM_020971.3(SPTBN4):c.3202_3203del (p.Ala1068fs)	Likely pathogenic

SpliceAI

5935 predictions. Top by Δscore:

Variant	Effect	Δscore
19:40472602:TCCA:T	acceptor_loss	1.0000
19:40472605:A:AG	acceptor_gain	1.0000
19:40472605:AG:A	acceptor_gain	1.0000
19:40472605:AGGC:A	acceptor_loss	1.0000
19:40472606:G:GG	acceptor_gain	1.0000
19:40472606:GG:G	acceptor_gain	1.0000
19:40472606:GGC:G	acceptor_gain	1.0000
19:40472606:GGCCT:G	acceptor_gain	1.0000
19:40487825:G:GT	donor_gain	1.0000
19:40487825:G:T	donor_gain	1.0000
19:40487845:GCTG:G	donor_gain	1.0000
19:40490296:A:T	donor_gain	1.0000
19:40493050:GCTGG:G	donor_gain	1.0000
19:40493051:C:G	donor_gain	1.0000
19:40493052:TGGG:T	donor_loss	1.0000
19:40493053:GG:G	donor_gain	1.0000
19:40493053:GGGTA:G	donor_loss	1.0000
19:40493054:GG:G	donor_gain	1.0000
19:40493055:G:GG	donor_gain	1.0000
19:40493056:TAAG:T	donor_loss	1.0000
19:40501912:T:TA	acceptor_gain	1.0000
19:40501916:TCCA:T	acceptor_loss	1.0000
19:40501917:CCAG:C	acceptor_loss	1.0000
19:40501919:A:AG	acceptor_gain	1.0000
19:40501919:AG:A	acceptor_loss	1.0000
19:40501920:G:GC	acceptor_gain	1.0000
19:40501920:GA:G	acceptor_gain	1.0000
19:40501920:GATGT:G	acceptor_gain	1.0000
19:40502018:G:GT	donor_gain	1.0000
19:40502018:G:T	donor_gain	1.0000

AlphaMissense

16525 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:40487735:T:A	W70R	1.000
19:40487735:T:C	W70R	1.000
19:40490103:T:C	I117T	1.000
19:40490119:C:A	N122K	1.000
19:40490119:C:G	N122K	1.000
19:40490133:T:C	L127P	1.000
19:40490220:T:C	L156P	1.000
19:40490225:T:A	W158R	1.000
19:40490225:T:C	W158R	1.000
19:40490227:G:C	W158C	1.000
19:40490227:G:T	W158C	1.000
19:40490238:T:C	L162P	1.000
19:40490243:T:C	F164L	1.000
19:40490245:C:A	F164L	1.000
19:40490245:C:G	F164L	1.000
19:40493024:T:C	L186P	1.000
19:40493032:T:A	W189R	1.000
19:40493032:T:C	W189R	1.000
19:40493034:G:C	W189C	1.000
19:40493034:G:T	W189C	1.000
19:40493035:T:C	C190R	1.000
19:40493037:T:G	C190W	1.000
19:40494934:T:A	W209R	1.000
19:40494934:T:C	W209R	1.000
19:40494943:G:C	G212R	1.000
19:40494944:G:A	G212D	1.000
19:40494944:G:T	G212V	1.000
19:40503836:T:C	F457L	1.000
19:40503838:T:A	F457L	1.000
19:40503838:T:G	F457L	1.000

dbSNP variants (sampled 300 via entrez): RS1000026918 (19:40546720 T>A), RS1000087727 (19:40504030 T>A,G), RS1000095790 (19:40554607 G>A,C,T), RS1000124056 (19:40513440 A>G), RS1000126250 (19:40570594 C>A,G,T), RS1000214108 (19:40563896 A>C), RS1000221535 (19:40570788 G>A), RS1000253527 (19:40560478 C>A,T), RS1000258898 (19:40522777 A>C,G), RS1000258933 (19:40475749 A>G), RS1000272114 (19:40479965 G>T), RS1000275042 (19:40469596 G>A), RS1000325148 (19:40552844 G>A), RS1000326433 (19:40564307 G>C), RS1000362659 (19:40567193 G>A)

Disease associations

OMIM: gene MIM:606214 | disease phenotypes: MIM:617519

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, neuropathy, and deafness	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, neuropathy, and deafness	Definitive	AR

Mondo (1): neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MONDO:0060496)

Orphanet (0):

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000407	Sensorineural hearing impairment
HP:0000666	Horizontal nystagmus
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001319	Neonatal hypotonia
HP:0001344	Absent speech
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002058	Myopathic facies
HP:0002194	Delayed gross motor development
HP:0002353	EEG abnormality
HP:0002421	Poor head control
HP:0002460	Distal muscle weakness
HP:0002500	Abnormal cerebral white matter morphology
HP:0002650	Scoliosis
HP:0003477	Peripheral axonal neuropathy
HP:0003554	Type 2 muscle fiber atrophy
HP:0003577	Congenital onset
HP:0003623	Neonatal onset
HP:0003693	Distal amyotrophy
HP:0003700	Generalized amyotrophy
HP:0004463	Absent brainstem auditory responses

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002804_5	Antibody level in response to infection	8.000000e-07
GCST007269_175	Pulse pressure	6.000000e-19
GCST009921_7	Carotid intima media thickness (mean)	1.000000e-10
GCST010083_320	Hemoglobin levels	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007034	seropositivity measurement
EFO:0007038	Influenza A seropositivity
EFO:0005763	pulse pressure measurement
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
CGP 52608	increases reaction, affects binding	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Cisplatin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Lead	affects expression	1
Niclosamide	increases expression	1
Phthalic Acids	decreases methylation	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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