NSD1

Chr 5AD

nuclear receptor binding SET domain protein 1

Also known as: ARA267, KMT3B, SOTOS, SOTOS1, STO

NCBI Gene: 64324 ENSG00000165671 UniProt: Q96L73 OMIM: 606681

This protein functions as a histone methyltransferase that enhances androgen receptor transactivation and acts as a bifunctional transcriptional regulator in the nucleus. Mutations cause Sotos syndrome and Weaver syndrome through an autosomal dominant inheritance pattern. The pathogenic mechanism involves loss of function, as the protein is highly intolerant to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgen receptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutations of this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocation with the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd on chromosome 11. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Sep 2018]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.101 OMIM phenotype

Clinical Summary— NSD1

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Gene-Disease Validity (ClinGen)

Sotos syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 9.31

OE 0.05 (0.02–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.41Z-score

OE missense 0.75 (0.71–0.79)

1065 obs / 1427.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.10)

0≤0.351.4

Missense OE?0.75 (0.71–0.79)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 5 / 110.6Missense obs/exp: 1065 / 1427.7Syn Z: 0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNSD1-related Sotos syndromeLOFAD

definitiveNSD1-related Beckwith-Wiedemann syndromeOTHERAD

This gene — mechanism propensity

0.2399th %ile

GOF

0.2398th %ile

LOF

0.86top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.10 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of NSD1 causes Sotos syndrome.1

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

References