SF1

Chr 11

splicing factor 1

Also known as: BBP, D11S636, MBBP, ZCCHC25, ZFM1, ZNF162

NCBI Gene: 7536 ENSG00000168066 UniProt: Q13285

This gene encodes a transcriptional activator that is essential for sexual differentiation and formation of primary steroidogenic tissues by regulating steroidogenic P450 genes and other key developmental genes. Mutations cause disorders of sex development with adrenal insufficiency, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants in the general population, consistent with its essential role in development.

GeneReviews ResearchSummary from RefSeq, UniProt

This gene encodes a nuclear pre-mRNA splicing factor. The encoded protein specifically recognizes the intron branch point sequence at the 3' splice site, together with the large subunit of U2 auxiliary factor (U2AF), and is required for the early stages of spliceosome assembly. It also plays a role in nuclear pre-mRNA retention and transcriptional repression. The encoded protein contains an N-terminal U2AF ligand motif, a central hnRNP K homology motif and quaking 2 region which bind a key branch-site adenosine within the branch point sequence, a zinc knuckles domain, and a C-terminal proline-rich domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProt46,XY sex reversal 3

UniProt46,XX sex reversal 4

UniProtAdrenal insufficiency, NR5A1-related

UniProtPremature ovarian failure 7

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

145

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — SF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 0.999

Z-score 4.54

OE 0.04 (0.01–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.62Z-score

OE missense 0.45 (0.39–0.51)

151 obs / 338.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.18)

0≤0.351.4

Missense OE?0.45 (0.39–0.51)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 1 / 25.9Missense obs/exp: 151 / 338.4Syn Z: -2.27

Background carrier burden — how many people carry a rare variant somewhere in SF1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 59

1,118 rare PASS variants

Rare truncating (LoF)

1 in 770

91 rare PASS variants

Rare synonymous (reference)

1 in 100

415 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SF1. 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 73	1 in 770
South Asian	~43k	1 in 54	1 in 560
Remaining (unassigned)	~30k	1 in 59	1 in 1,700
European (Finnish)	~27k	1 in 130	1 in 1,300
Admixed American	~22k	1 in 46	1 in 2,700
African / African American	~21k	1 in 62	1 in 2,100
East Asian	~20k	1 in 58	1 in 1,700
Ashkenazi Jewish	~13k	1 in 190	1 in 1,000
Middle Eastern	~2,884	1 in 64	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 13 coding exons well covered in gnomAD exomes; exons 1, 12 marginal. Genomes: 12 of 13 (exon 13 below).? see exons ↓