NSD3

Chr 8

nuclear receptor binding SET domain protein 3

Also known as: KMT3F, KMT3G, WHISTLE, WHSC1L1, pp14328

NCBI Gene: 54904 ENSG00000147548 UniProt: Q9BZ95 OMIM: 607083

This gene is related to the Wolf-Hirschhorn syndrome candidate-1 gene and encodes a protein with PWWP (proline-tryptophan-tryptophan-proline) domains. This protein methylates histone H3 at lysine residues 4 and 27, which represses gene transcription. Two alternatively spliced variants have been described. [provided by RefSeq, May 2015]

OMIM Research

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.14

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 7.44

OE 0.07 (0.03–0.14)

Highly constrained

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

Missense Constraint?

3.73Z-score

OE missense 0.62 (0.58–0.67)

483 obs / 775.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.14)

0≤0.351.4

Missense OE?0.62 (0.58–0.67)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 5 / 74.1Missense obs/exp: 483 / 775.2Syn Z: 1.47

Background carrier burden — how many people carry a rare variant somewhere in NSD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

1,257 rare PASS variants

Rare truncating (LoF)

1 in 6,500

55 rare PASS variants

Rare synonymous (reference)

1 in 81

563 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NSD3. 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 92	1 in 9,800
South Asian	~43k	1 in 53	1 in 2,900
Remaining (unassigned)	~30k	1 in 59	none seen
European (Finnish)	~27k	1 in 140	≈ 1 in 26,000
Admixed American	~22k	1 in 56	≈ 1 in 22,000
African / African American	~21k	1 in 77	≈ 1 in 4,900
East Asian	~20k	1 in 74	1 in 1,600
Ashkenazi Jewish	~13k	1 in 500	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 54	none seen

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): 22 of 23 coding exons well covered in gnomAD exomes; exon 20 marginal. Genomes: all 23.? see exons ↓