SPEN

Chr 1AD

spen family transcriptional repressor

Also known as: HIAA0929, MINT, RATARS, RBM15C, SHARP

NCBI Gene: 23013 ENSG00000065526 UniProt: Q96T58 OMIM: 613484

This gene encodes a transcriptional repressor that regulates key developmental pathways including Notch signaling and serves as a nuclear matrix platform organizing transcriptional responses. Mutations cause Radio-Tartaglia syndrome, an autosomal dominant disorder characterized by intellectual disability, distinctive facial features, and skeletal abnormalities. The gene is highly constrained against loss-of-function variation (pLI=1, LOEUF=0.071), indicating that complete loss of protein function is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Radio-Tartaglia syndromeMIM #619312

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Radio-Tartaglia syndrome · AD · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

LOF

Mechanism· G2P

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GeneReview available — SPEN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

gnomad: Error: gnomAD API error: 400

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in SPEN?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 14

4,166 rare PASS variants

Rare truncating (LoF)

1 in 1,200

118 rare PASS variants

Rare synonymous (reference)

1 in 25

1,864 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPEN. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 17	1 in 1,200
South Asian	~43k	1 in 14	1 in 1,600
Remaining (unassigned)	~30k	1 in 14	1 in 2,000
European (Finnish)	~27k	1 in 44	1 in 450
Admixed American	~22k	1 in 16	1 in 770
African / African American	~21k	1 in 18	1 in 1,300
East Asian	~20k	1 in 17	1 in 1,100
Ashkenazi Jewish	~13k	1 in 66	1 in 2,100
Middle Eastern	~2,884	1 in 15	1 in 480

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 15 coding exons well covered in gnomAD exomes; exons 1, 8, 9 marginal. Genomes: all 15.? see exons ↓