NSD2

Chr 4AD

nuclear receptor binding SET domain protein 2

Also known as: KMT3F, KMT3G, MMSET, RAUST, REIIBP, TRX5, WHS, WHSC1

NCBI Gene: 7468 ENSG00000109685 UniProt: O96028 OMIM: 602952

The protein encoded by this gene is a histone methyltransferase that contains PWWP, HMG box, SET, and PHD domains and functions in chromatin modification during early development. Loss-of-function mutations cause Rauch-Steindl syndrome through an autosomal dominant inheritance pattern. The gene is also located within the Wolf-Hirschhorn syndrome critical region on chromosome 4p16.3 and contributes to the malformation phenotype seen with deletions of this chromosomal region.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that contains four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger. It is expressed ubiquitously in early development. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene maps to the 165 kb WHS critical region and has also been involved in the chromosomal translocation t(4;14)(p16.3;q32.3) in multiple myelomas. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Some transcript variants are nonsense-mediated mRNA (NMD) decay candidates, hence not represented as reference sequences. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— NSD2

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · 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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 7.14

OE 0.05 (0.02–0.12)

Highly constrained

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

Missense Constraint?

3.90Z-score

OE missense 0.61 (0.57–0.66)

498 obs / 810.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.12)

0≤0.351.4

Missense OE?0.61 (0.57–0.66)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 3 / 65.3Missense obs/exp: 498 / 810.2Syn Z: -1.94

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNSD2-related developmental disorderLOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.2497th %ile

LOF

0.82top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.12 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFNSD2 haploinsufficiency causes Wolf-Hirschhorn syndrome, while NSD1 mutations lead to the 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