SPEN

spen family transcriptional repressor, the group of RNA binding motif containing

Basic information

Region (hg38): 1:15836095-15940456

Links

ENSG00000065526 ∙ NCBI:23013 ∙ OMIM:613484 ∙ HGNC:17575 ∙ Uniprot:Q96T58 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (No Known Disease Relationship), mode of inheritance: AD
• Radio-Tartaglia syndrome (Strong), mode of inheritance: AD
• Radio-Tartaglia syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Radio-Tartaglia syndrome	AD	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic	33596411

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPEN gene.

• not provided (30 variants)
• Radio-Tartaglia syndrome (12 variants)
• Inborn genetic diseases (9 variants)
• Neurodevelopmental abnormality (1 variants)
• Neurodevelopmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPEN gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				58	11	69
missense			248	68	19	335
nonsense	20	8	3			31
start loss						0
frameshift	26	8	1			35
inframe indel			8	2	3	13
splice donor/acceptor (+/-2bp)						0
splice region			1	2	2	5
non coding				2		2
Total	46	16	260	130	33

Variants in SPEN

This is a list of pathogenic ClinVar variants found in the SPEN region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-15848067-C-T		SPEN-related disorder	Likely benign (Dec 11, 2019)
1-15848091-C-T			Likely benign (Sep 01, 2022)
1-15848137-G-A		Radio-Tartaglia syndrome	Uncertain significance (Jul 21, 2023)
1-15848139-G-C			Uncertain significance (Apr 16, 2022)
1-15872824-G-A		Developmental disorder • Radio-Tartaglia syndrome	Conflicting classifications of pathogenicity (Apr 09, 2021)
1-15872825-C-T		SPEN-related disorder	Likely benign (Apr 11, 2019)
1-15872832-A-G			Uncertain significance (Nov 17, 2021)
1-15872841-A-G		Radio-Tartaglia syndrome	Uncertain significance (Sep 28, 2022)
1-15873007-A-G		Radio-Tartaglia syndrome	Uncertain significance (Dec 21, 2023)
1-15873031-G-A		Inborn genetic diseases	Uncertain significance (Apr 24, 2023)
1-15873033-A-G		SPEN-related disorder	Uncertain significance (Apr 18, 2023)
1-15873058-G-A			Uncertain significance (Nov 01, 2022)
1-15873067-G-C		Inborn genetic diseases	Uncertain significance (Sep 06, 2022)
1-15873083-T-C			Likely benign (Oct 01, 2022)
1-15873105-C-T		Inborn genetic diseases	Pathogenic (Dec 17, 2021)
1-15873124-G-A			Uncertain significance (Nov 01, 2023)
1-15873125-G-A		SPEN-related disorder	Likely benign (Oct 01, 2023)
1-15873135-G-A		Inborn genetic diseases	Uncertain significance (Oct 12, 2021)
1-15874303-C-T			Likely benign (Jan 01, 2023)
1-15876215-A-G		Inborn genetic diseases	Uncertain significance (Jun 11, 2021)
1-15876221-C-T		SPEN-related disorder	Uncertain significance (Jul 13, 2024)
1-15876252-A-C			Uncertain significance (Dec 13, 2022)
1-15876264-C-T		Inborn genetic diseases	Uncertain significance (Apr 29, 2024)
1-15876275-G-A		not specified	Benign (May 04, 2022)
1-15876293-G-A			Uncertain significance (Dec 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPEN	protein_coding	protein_coding	ENST00000375759	15	92597

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.46e-18	125730	0	18	125748	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.89	1697	2.07e+3	0.821	0.000124	23759
Missense in Polyphen		659	975.57	0.6755		11054
Synonymous	-0.323	822	810	1.01	0.0000501	7710
Loss of Function	10.2	4	129	0.0310	0.00000872	1443

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000120	0.000120
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.000185	0.000185
European (Non-Finnish)	0.0000880	0.0000791
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May serve as a nuclear matrix platform that organizes and integrates transcriptional responses. In osteoblasts, supports transcription activation: synergizes with RUNX2 to enhance FGFR2- mediated activation of the osteocalcin FGF-responsive element (OCFRE) (By similarity). Has also been shown to be an essential corepressor protein, which probably regulates different key pathways such as the Notch pathway. Negative regulator of the Notch pathway via its interaction with RBPSUH, which prevents the association between NOTCH1 and RBPSUH, and therefore suppresses the transactivation activity of Notch signaling. Blocks the differentiation of precursor B-cells into marginal zone B-cells. Probably represses transcription via the recruitment of large complexes containing histone deacetylase proteins. May bind both to DNA and RNA. {ECO:0000250, ECO:0000269|PubMed:11331609, ECO:0000269|PubMed:12374742}.
• Pathway: Notch Signaling Pathway;Notch;Notch;Notch signaling pathway;Notch-mediated HES/HEY network (Consensus)

Recessive Scores

• pRec: 0.160

Intolerance Scores

• loftool: 0.206
• rvis_EVS: -2.31
• rvis_percentile_EVS: 1.21

Haploinsufficiency Scores

• pHI: 0.878
• hipred: Y
• hipred_score: 0.775
• ghis: 0.606

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.859

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Spen
• Phenotype: liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;Notch signaling pathway;viral process;negative regulation of transcription, DNA-templated;positive regulation of neurogenesis
• Cellular component: nucleus;nucleoplasm;transcriptional repressor complex;extracellular exosome
• Molecular function: RNA polymerase II transcription factor binding;DNA binding;transcription corepressor activity;RNA binding;protein binding