DNMT3L

Chr 21

DNA methyltransferase 3 like

NCBI Gene: 29947 ENSG00000142182 UniProt: Q9UJW3 OMIM: 606588

DNMT3L encodes a catalytically inactive regulatory factor that activates DNA methyltransferases DNMT3A and DNMT3B, playing essential roles in establishing genomic imprints and methylating retrotransposons in germ cells. The gene is not highly constrained against loss-of-function variants (pLI ~0, LOEUF 1.3), and mutations cause maternal-effect lethal overgrowth syndrome, characterized by fetal overgrowth and pregnancy complications. This condition follows an autosomal recessive inheritance pattern affecting maternal oocyte function.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.30

LOEUF

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Mechanism

📖

GeneReview available — DNMT3L

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.30LOEUF

pLI 0.000

Z-score 0.47

OE 0.89 (0.63–1.30)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.10Z-score

OE missense 0.98 (0.88–1.09)

237 obs / 241.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.63–1.30)

0≤0.351.4

Missense OE?0.98 (0.88–1.09)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 20 / 22.4Missense obs/exp: 237 / 241.5Syn Z: 0.63

Background carrier burden — how many people carry a rare variant somewhere in DNMT3L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

327 rare PASS variants

Rare truncating (LoF)

1 in 1,200

65 rare PASS variants

Rare synonymous (reference)

1 in 140

125 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DNMT3L. 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 220	1 in 1,100
South Asian	~43k	1 in 210	1 in 1,800
Remaining (unassigned)	~30k	1 in 120	1 in 820
European (Finnish)	~27k	1 in 410	1 in 1,300
Admixed American	~22k	1 in 160	≈ 1 in 5,600
African / African American	~21k	1 in 130	1 in 1,500
East Asian	~20k	1 in 150	1 in 2,500
Ashkenazi Jewish	~13k	1 in 870	none seen
Middle Eastern	~2,884	1 in 220	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): 7 of 11 coding exons well covered in gnomAD exomes; exons 9, 10, 11, 12 poorly covered. Genomes: 7 of 11 (exons 9, 10, 11, 12 below).? see exons ↓