SPEN

protein-coding

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

Gene summary

This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015001.3

Inheritance

ClinVar variants

P:119U:650B:281

Top phenotype

Radio-Tartaglia syndrome

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr1:15,836,095-15,940,456

External References & Databases

Ensembl (ENSG00000065526)

Transcript & Mutation Effects

hg38 • Region Span ~104.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Radio-Tartaglia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859143

Submitter: ClinGen

The SPEN gene is located on chromosome 1 at 1p36.21-p36.13 and appears to function as a nuclear matrix platform that organizes and integrates transcriptional responses, and is thought to be involved in chromatin remodeling. SPEN was first reported in relation to autosomal dominant SPEN-related neurodevelopmental disorder in 2021 by Radio et al. (PMID: 33596411). The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, behavioral abnormalities, hypotonia, brain and spine anomalies, congenital heart defects, gait imbalance, variable facial dysmorphisms, and obesity/increased BMI, especially in females. This curation included 7 unique truncating variants (4 nonsense and 3 frameshift) in 7 probands from 1 publication (PMID: 33596411). The majority of cases showed de novo inheritance, but familial inheritance in one family was scored. Note there are additional unpublished cases. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including expression in the developing human neocortex and several animal models (Drosophila and conditional knockout mouse) in which inactivation of SPEN was associated with a neuronal phenotype (PMIDs: 10704397, 17457934). In summary, there is definitive evidence supporting the relationship between SPEN and autosomal dominant SPEN-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 11/01/2023.

Radio-Tartaglia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859143

Submitter: PanelApp Australia

Radio-Tartaglia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859143

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Illumina

Radio-Tartaglia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859143

Submitter: G2P

Clinical Genomic Database (CGD)

Radio-Tartaglia syndromeAD

Manifestation: Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 33596411

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPEN variants in ClinVar

16 Conditions Cataloged

not providedTotal: 437

Inborn genetic diseasesTotal: 411

SPEN-related disorderTotal: 148

Radio-Tartaglia syndromeTotal: 129

not specifiedTotal: 84

See casesTotal: 5

Autism spectrum disorderTotal: 4

Neurodevelopmental delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015001.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	126 clinvar	6 clinvar	138
missense	1 clinvar		629 clinvar	133 clinvar	16 clinvar	779
nonsense	24 clinvar	22 clinvar	6 clinvar			52
start loss						0
frameshift	41 clinvar	30 clinvar	3 clinvar			74
splice donor/acceptor (+/-2bp)	1 clinvar		6 clinvar			7
Total	67	52	650	259	22	1050

Highest pathogenic variant AF is 0.0000065733257

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015001.3	RefSeq	NP_055816.2	15	MANE Select
ENST00000375759.8	Ensembl	ENSP00000364912.3	15	MANE Select
ENST00000438066.2	Ensembl	ENSP00000388021.2	2	Standard
ENST00000442985.1	Ensembl	ENSP00000400914.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Notch Signaling Pathway
Notch
Notch
Notch signaling pathway
Notch-mediated HES/HEY network

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

Molecular Function

RNA polymerase II transcription factor binding
DNA binding
transcription corepressor activity
RNA binding
protein binding

Cellular Component

nucleus
nucleoplasm
transcriptional repressor complex
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375759
Coding exons: 15
Length: 92597
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.89	1697	2.07e+3	0.821	0.000124	23759
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.000088	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.206
RVIS EVS: -2.31
RVIS percentile EVS: 1.21

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.859

Gene Damage Prediction

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