HECTD3

Chr 1

HECT domain E3 ubiquitin protein ligase 3

NCBI Gene: 79654 ENSG00000126107 UniProt: Q5T447 OMIM: 618638

The protein functions as an E3 ubiquitin ligase that transfers ubiquitin to target substrates including TRIOBP and STX8, leading to their proteasomal degradation and facilitating cell cycle progression. Mutations cause neurodevelopmental disorders with intellectual disability, autism spectrum disorder, and seizures, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.403), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene transfers ubiquitin from an E2 ubiquitin-conjugating enzyme to targeted substrates, leading to the degradation of those substrates. The encoded protein has been shown to transfer ubiquitin to TRIOBP to facilitate cell cycle progression, and to STX8. [provided by RefSeq, Dec 2012]

OMIM ResearchGenerating clinical summary…

LOEUF 0.40

Clinical Summary— HECTD3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

106 VUS of 131 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.089

Z-score 4.83

OE 0.25 (0.16–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.15Z-score

OE missense 0.73 (0.67–0.80)

367 obs / 502.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.40)

0≤0.351.4

Missense OE?0.73 (0.67–0.80)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 12 / 48.2Missense obs/exp: 367 / 502.6Syn Z: 0.59

ClinVar Variant Classifications

131 submitted variants in ClinVar

ClinVar

Classification Summary

VUS106

Likely Benign5

Benign3

106

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	105	0	106
Likely Benign	0	3	2	5
Benign	0	1	2	3
Total	1	109	4	114

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap HECTD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →