NDST1

protein-coding

N-deacetylase and N-sulfotransferase 1, the group of Sulfotransferases, membrane bound

Gene summary

This gene encodes a member of the heparan sulfate/heparin GlcNAc N-deacetylase/ N-sulfotransferase family. The encoded enzyme is a type II transmembrane protein that resides in the Golgi apparatus. The encoded protein catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to nitrogen of glucosamine in heparan sulfate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Previous symbols:

HSST

MANE transcript

NM_001543.5

Inheritance

ClinVar variants

P:6U:172B:97

Top phenotype

Intellectual developmental disorder, autosomal recessive 46

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr5:150,485,818-150,558,211

External References & Databases

Ensembl (ENSG00000070614)

Transcript & Mutation Effects

hg38 • Region Span ~72.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 46STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014499

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 46MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014499

Submitter: Ambry Genetics

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 46STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014499

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 46AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21937992; 25125150

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDST1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 173

Inborn genetic diseasesTotal: 111

not specifiedTotal: 73

Intellectual disability, autosomal recessive 46Total: 23

NDST1-related disorderTotal: 17

Intellectual disabilityTotal: 5

NDST1-related disordersTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001543.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	83 clinvar	5 clinvar	91
missense	2 clinvar	4 clinvar	163 clinvar	9 clinvar		178
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	2	4	172	92	5	275

Highest pathogenic variant AF is 0.000043985725

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001543.5	RefSeq	NP_001534.1	14	MANE Select
ENST00000261797.7	Ensembl	ENSP00000261797.6	14	MANE Select
NM_001301063.2	RefSeq	NP_001287992.1	13	Standard
ENST00000518299.1	Ensembl	ENSP00000430258.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ndst1a	Danio rerio	Structure: basihyal cartilage Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

ndst1a

Danio rerio

Structure: basihyal cartilage

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human)
Metapathway biotransformation Phase I and II
Metabolism of carbohydrates
HS-GAG biosynthesis
Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

glycosaminoglycan biosynthetic process
protein sulfation
inflammatory response
heparan sulfate proteoglycan biosynthetic process
heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process

Molecular Function

protein binding
[heparan sulfate]-glucosamine N-sulfotransferase activity
deacetylase activity
heparan sulfate sulfotransferase activity
heparan sulfate N-acetylglucosaminyltransferase activity

Cellular Component

Golgi membrane
Golgi apparatus
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261797
Coding exons: 14
Length: 72393
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.92	353	545	0.648	0.0000377	5778
Missense (PolyPhen)		109	223.52	0.48765		2347
Synonymous	-0.126	247	245	1.01	0.0000183	1771
Loss of Function	5.54	3	41.5	0.0722	0.00000237	435

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000037	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential bifunctional enzyme that catalyzes both the N- deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate. Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis (PubMed:10758005, PubMed:12634318). Plays a role in determining the extent and pattern of sulfation of heparan sulfate. Compared to other NDST enzymes, its presence is absolutely required. Participates in biosynthesis of heparan sulfate that can ultimately serve as L-selectin ligands, thereby playing a role in inflammatory response (PubMed:10758005, PubMed:12634318). Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). {ECO:0000269|PubMed:10758005, ECO:0000269|PubMed:12634318, ECO:0000269|PubMed:22660413}.;

Recessive Scores

pRec: 0.185

Intolerance Scores

LoFtool: 0.0415
RVIS EVS: -1.75
RVIS percentile EVS: 2.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.500

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium