SALL1

Chr 16AD

spalt like transcription factor 1

Also known as: HEL-S-89, HSAL1, Sal-1, TBS, ZNF794

NCBI Gene: 6299 ENSG00000103449 UniProt: Q9NSC2

The protein encoded by this gene is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase complex (HDAC). Defects in this gene are a cause of Townes-Brocks syndrome (TBS) as well as bronchio-oto-renal syndrome (BOR). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Townes-Brocks branchiootorenal-like syndromeMIM #107480

Townes-Brocks syndrome 1MIM #107480

Active trials

Pathogenic / LP

375

ClinVar variants

Pubs (1 yr)

0.7

Missense Z

0.20

LOEUF· LoF intolerant

Clinical Summary— SALL1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

58 Pathogenic / Likely Pathogenic· 202 VUS of 375 total submissions

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GeneReview available — SALL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.20LOEUF

pLI 1.000

Z-score 4.92

OE 0.06 (0.02–0.20)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.72Z-score

OE missense 0.93 (0.87–0.99)

687 obs / 742.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.20)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.87–0.99)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04

0≤1.21.6

LoF obs/exp: 2 / 32.1Missense obs/exp: 687 / 742.3Syn Z: -0.50

0.3395th %ile

GOF

0.2397th %ile

LOF

0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 48% of P/LP variants are LoF · LOEUF 0.20

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNOver 60 nonsense and frameshift mutations have been identified in SALL1, the zinc finger transcription factor causing TBS, and are proposed to cause disease via a dominant negative mechanism.PMID:22308078

GOFSince the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein.PMID:12915476

LOFTruncating mutations of SALL1 have been shown to cause Townes-Brocks syndrome and are thought to result in SALL1 haploinsufficiency.PMID:10610715

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.