KMT5B

Chr 11

lysine methyltransferase 5B

Also known as: CGI-85, CGI85, MRD51, SUV420H1

NCBI Gene: 51111 ENSG00000110066 UniProt: Q4FZB7

The protein is a histone methyltransferase that specifically methylates lysine-20 of histone H4 to regulate transcriptional repression, heterochromatin formation, and DNA repair. Heterozygous loss-of-function mutations cause autosomal dominant intellectual developmental disorder through haploinsufficiency. The gene is highly intolerant to loss-of-function variants, consistent with dominant negative effects from reduced histone methylation activity.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that contains a SET domain. SET domains appear to be protein-protein interaction domains that mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). The function of this gene has not been determined. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtIntellectual developmental disorder, autosomal dominant 51

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2022

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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.08

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.08LOEUF

pLI 1.000

Z-score 5.72

OE 0.00 (0.00–0.08)

Highly constrained

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

Missense Constraint?

2.79Z-score

OE missense 0.64 (0.58–0.70)

306 obs / 477.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.08)

0≤0.351.4

Missense OE?0.64 (0.58–0.70)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 0 / 38.1Missense obs/exp: 306 / 477.5Syn Z: 1.46

Background carrier burden — how many people carry a rare variant somewhere in KMT5B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

807 rare PASS variants

Rare truncating (LoF)

1 in 2,100

33 rare PASS variants

Rare synonymous (reference)

1 in 140

372 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KMT5B. 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 78	1 in 2,600
South Asian	~43k	1 in 93	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 64	1 in 2,500
European (Finnish)	~27k	1 in 160	≈ 1 in 27,000
Admixed American	~22k	1 in 90	≈ 1 in 21,000
African / African American	~21k	1 in 59	none seen
East Asian	~20k	1 in 95	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 280	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 62	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): 9 of 10 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 10.? see exons ↓