GeneBe

PAPSS2

protein-coding

3'-phosphoadenosine 5'-phosphosulfate synthase 2

Gene summary

Sulfation is a common modification of endogenous (lipids, proteins, and carbohydrates) and exogenous (xenobiotics and drugs) compounds. In mammals, the sulfate source is 3'-phosphoadenosine 5'-phosphosulfate (PAPS), created from ATP and inorganic sulfate. Two different tissue isoforms encoded by different genes synthesize PAPS. This gene encodes one of the two PAPS synthetases. Defects in this gene cause the Pakistani type of spondyloepimetaphyseal dysplasia. Two alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001015880.2

Inheritance

AR

ClinVar variants

P:43U:160B:83

Top phenotype

Brachyolmia 4 with mild epiphyseal and metaphyseal changes

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr10:87,659,613-87,747,705

External References & Databases

Ensembl (ENSG00000198682)NCBI Gene (9060)OMIM (603005)HGNC:8604GenCCUniProt (O95340)AlphaFoldClinVar (PAPSS2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~88.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spondyloepimetaphyseal dysplasia, PAPSS2 typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019666

Submitter: PanelApp Australia

spondyloepimetaphyseal dysplasia, PAPSS2 typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019666

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, PAPSS2 typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019666

Submitter: Ambry Genetics

spondyloepimetaphyseal dysplasia, PAPSS2 typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019666

Submitter: Orphanet

spondyloepimetaphyseal dysplasia, PAPSS2 typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019666

Submitter: G2P

autosomal recessive brachyolmiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018662

Submitter: Orphanet

Clinical Genomic Database (CGD)

Brachyolmia 4 with mild epiphyseal and metaphyseal changesAR

Manifestation: Endocrine; Musculoskeletal

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

Comments: The condition may include endocrinological manifestations such as premature pubarche

Refs: 9714015; 9771708; 19474428Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PAPSS2 variants in ClinVar

9 Conditions Cataloged
Spondyloepimetaphyseal dysplasia, PAPSS2 typeTotal: 268
Inborn genetic diseasesTotal: 89
not providedTotal: 73
not specifiedTotal: 32
PAPSS2-related disorderTotal: 15
Fetal anomalies with a likely genetic causeTotal: 3
Skeletal dysplasiaTotal: 1
Autosomal recessive brachyolmiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001015880.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
72
clinvar
2
clinvar
 75
missense
3
clinvar
1
clinvar
151
clinvar
7
clinvar
2
clinvar
 164
nonsense
13
clinvar
3
clinvar
 16
start loss
0
frameshift
10
clinvar
6
clinvar
2
clinvar
 18
splice donor/acceptor (+/-2bp)
3
clinvar
4
clinvar
6
clinvar
 13
Total2914160794286

Highest pathogenic variant AF is 0.0006004253

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001015880.2RefSeqNP_001015880.113MANE Select
ENST00000456849.2EnsemblENSP00000406157.113MANE Select
NM_004670.4RefSeqNP_004661.212Standard
ENST00000361175.8EnsemblENSP00000354436.412Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Selenocompound metabolism - Homo sapiens (human)
  • Purine metabolism - Homo sapiens (human)
  • Sulfur metabolism - Homo sapiens (human)
  • Sulfate/Sulfite Metabolism
  • Sulfite oxidase deficiency

Biological Process

  • sulfate assimilation
  • skeletal system development
  • blood coagulation
  • phosphorylation
  • 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process

Molecular Function

  • adenylylsulfate kinase activity
  • sulfate adenylyltransferase (ATP) activity
  • ATP binding
  • nucleotidyltransferase activity

Cellular Component

  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000456849
Coding exons
13
Length
88093
Individuals with no LoFs
125684
Homozygous LoFs
0
Heterozygous LoFs
64
Defined
125748
p
0.000255
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.4613273510.9310.00002114062
Missense (PolyPhen)133154.130.86291731
Synonymous-0.9571441301.110.000007591217
Loss of Function1.752030.40.6580.00000174346

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000740.00074rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000160.00016rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000260.00025rare
South Asian0.000430.00042rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate (PAPS: activated sulfate donor used by sulfotransferase). In mammals, PAPS is the sole source of sulfate; APS appears to be only an intermediate in the sulfate- activation pathway. May have a important role in skeletogenesis during postnatal growth (By similarity). {ECO:0000250}.;

Recessive Scores

pRec
0.168

Intolerance Scores

LoFtool
0.891
RVIS EVS
-0.33
RVIS percentile EVS
30.74

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.929

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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