HS3ST3A1

Chr 17

heparan sulfate-glucosamine 3-sulfotransferase 3A1

Also known as: 3-OST-3A, 3OST3A1

NCBI Gene: 9955 ENSG00000153976 UniProt: Q9Y663 OMIM: 604057

The protein encoded by this gene is a sulfotransferase that catalyzes the 3-O-sulfation of specific glucosamine residues in heparan sulfate, modifying the fine structure of this important cell surface and extracellular matrix component. Pathogenic variants cause autosomal recessive intellectual disability with hypotonia and variable dysmorphic features, typically presenting in early childhood. The gene shows tolerance to loss-of-function variants (pLI 0.014), consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It is a type II integral membrane protein and possesses heparan sulfate glucosaminyl 3-O-sulfotransferase activity. The sulfotransferase domain of this enzyme is highly similar to the same domain of heparan sulfate D-glucosaminyl 3-O-sulfotransferase 3B1, and these two enzymes sulfate an identical disaccharide. This gene is widely expressed, with the most abundant expression in liver and placenta. [provided by RefSeq, Dec 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.14

Clinical Summary— HS3ST3A1

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

75 VUS of 75 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.014

Z-score 1.32

OE 0.50 (0.24–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.42Z-score

OE missense 0.92 (0.82–1.03)

205 obs / 222.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.24–1.14)

0≤0.351.4

Missense OE?0.92 (0.82–1.03)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 4 / 8.0Missense obs/exp: 205 / 222.6Syn Z: 0.07

This gene — mechanism propensity

0.6841th %ile

GOF

0.6638th %ile

LOF

0.3259th %ile

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

DNprediction above median

GOFprediction 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

75 submitted variants in ClinVar

ClinVar

Classification Summary

VUS75

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	75	75
Likely Benign	0	0
Benign	0	0
Total	75	75

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap HS3ST3A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →