Intellectual disability
Gene: SF1

SF1 (splicing factor 1)
EnsemblGeneIds (GRCh38): ENSG00000168066
EnsemblGeneIds (GRCh37): ENSG00000168066
OMIM: 601516, Gene2Phenotype
SF1 is in 2 panels

2 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are fifteen unrelated patients reported with monoallelic SF1 variants and a neurodevelopmental disorder, of which four patients had intellectual disability of moderate severity. Hence, this gene can be promoted to green rating in the next update.
Created: 9 Oct 2025, 12:27 p.m. | Last Modified: 9 Oct 2025, 12:27 p.m.

Panel Version: 9.121

As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v4.1.0 non-UK Biobank, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Created: 9 Oct 2025, 12:15 p.m. | Last Modified: 9 Oct 2025, 12:25 p.m.

Panel Version: 9.120

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071

Publications

40987292

Created: 9 Oct 2025, 12:15 p.m.
Last Modified: 9 Oct 2025, 12:25 p.m.
Panel version: 9.118

Mike Spiller (Sheffield Children's Hospital)

Green List (high evidence)

Gene-disease associated reported in PMID: 40987292.
15 patients with varying levels of global developmental delay and ASD. One of these is intronic with gnomad AC = 9 so can be disregarded.
Of the remaining 14 almost all are de novo. 13 absent from gnomad, 1 with AC = 1.
7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations. 6/7 missenses at conserved residues within missense-constrained regions, but no hotspot cluster..

NMD variants show the most consistent phenotype of mild-moderate ID/GDD.
Of the total 14 cases ID/GDD mild in 5, moderate in 4, level not stated in 5. Language delays most consistent characteristic..

Functional studies using SF1 knockdown in neural progenitor cells show substantial effects on gene regulation and alternative splicing, consistent with SF1 loss of function. However paper does not record if this led to any effects on NPC function.

Gene constrained for LOF (gnomad v4 o/e 0.12, LOEUF 0.22).
Sources: Literature
Created: 2 Oct 2025, 8:30 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

PMID: 40987292

Created: 2 Oct 2025, 8:30 a.m.

Panel version: 9.105

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Amber

Phenotypes

neurodevelopmental disorder, MONDO:0700092
intellectual disability, MONDO:0001071

Tags

Q3_25_promote_green Q3_25_NHS_review

OMIM

601516

Clinvar variants

Variants in SF1

Penetrance

None

Publications

40987292

Panels with this gene