SMYD3

Chr 1

SET and MYND domain containing 3

Also known as: KMT3E, ZMYND1, ZNFN3A1, bA74P14.1

NCBI Gene: 64754 ENSG00000185420 UniProt: Q9H7B4

This gene encodes a histone methyltransferase that specifically methylates lysine-4 of histone H3 and lysine-5 of histone H4, functioning as part of RNA polymerase II complexes to regulate transcriptional activation. Mutations cause autosomal dominant developmental delays and intellectual disability with onset in early childhood. The gene is not highly constrained against loss-of-function variants.

ResearchSummary from RefSeq, UniProt

This gene encodes a histone methyltransferase which functions in RNA polymerase II complexes by an interaction with a specific RNA helicase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.90

Clinical Summary— SMYD3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

63 VUS of 85 total submissions

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

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 1.96

OE 0.58 (0.39–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.24Z-score

OE missense 0.96 (0.86–1.07)

225 obs / 235.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.39–0.90)

0≤0.351.4

Missense OE?0.96 (0.86–1.07)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 25.7Missense obs/exp: 225 / 235.6Syn Z: -0.04

This gene — mechanism propensity

0.6744th %ile

GOF

0.6931th %ile

LOF

0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

85 submitted variants in ClinVar

ClinVar

Classification Summary

VUS63

Benign2

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	61	2	0	63
Likely Benign	0	0	0	0
Benign	0	1	1	2
Total	61	3	1	65

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

View in ClinVar →

81 pathogenic / likely-pathogenic (of 156) ClinVar copy-number / structural variants overlap SMYD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →