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…

LOFmechanismLOEUF 0.08

Clinical Summary— KMT5B

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · 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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ClinVar Variants

76 unique Pathogenic / Likely Pathogenic· 122 VUS of 268 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKMT5B-related intellectual developmental disorderLOFAD

This gene — mechanism propensity

0.2099th %ile

GOF

0.1699th %ile

LOF

0.88top 5%

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

LOFprediction above median · 1 literature citation · 80% of P/LP variants are LoF · LOEUF 0.08 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFWe provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders.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

1.PMID 29276005 ↗

ClinVar Variant Classifications

268 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic44

VUS122

Likely Benign46

Benign6

Conflicting8

Pathogenic

Likely Pathogenic

122

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	2	0	0	32
Likely Pathogenic	31	12	1	0	44
VUS	8	107	7	0	122
Likely Benign	1	23	2	20	46
Benign	0	3	1	2	6
Conflicting	—				8
Total	70	147	11	22	258

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap KMT5B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →