BPNT2

protein-coding

3'(2'), 5'-bisphosphate nucleotidase 2

Gene summary

This gene encodes a member of the inositol monophosphatase family. The encoded protein is localized to the Golgi apparatus and catalyzes the hydrolysis of phosphoadenosine phosphate (PAP) to adenosine monophosphate (AMP). Mutations in this gene are a cause of GRAPP type chondrodysplasia with joint dislocations, and a pseudogene of this gene is located on the long arm of chromosome 1. [provided by RefSeq, Dec 2011]

Previous symbols:

IMPAD1

MANE transcript

NM_017813.5

Inheritance

ClinVar variants

P:12U:91B:50

Top phenotype

Chondrodysplasia with joint dislocations, GPAPP type

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr8:56,957,931-56,993,867

External References & Databases

Ensembl (ENSG00000104331)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

chondrodysplasia with joint dislocations, gPAPP typeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013561

Submitter: ClinGen

BPNT2 was first reported in relation to autosomal recessive Chondrodysplasia with joint dislocations GPAPP type (MONDO:0013561) in 2011 (Vissers LE et al., 2011; PMID:21549340). GPAPP deficiency is a genetic, primary bone dysplasia characterized by prenatal onset of disproportionate short stature, shortening of the limbs, congenital joint dislocations, micrognathia, posterior cleft palate, brachydactyly, short metacarpals and irregular size of the metacarpal epiphyses, supernumerary carpal ossification centers and dysmorphic facial features. In addition, hearing impairment and mild psychomotor delay have also been reported. The disease can be caused by homozygous mutation in the BPNT2 gene (614078) on chromosome 8q12.1. This gene encodes a member of the inositol monophosphatase family. The encoded protein is localized to the Golgi apparatus and catalyzes the hydrolysis of phosphoadebbnosine phosphate (PAP) to adenosine monophosphate (AMP). Mutations in this gene are a cause of GRAPP type chondrodysplasia with joint dislocations, and a pseudogene of this gene is on the long arm of chromosome 1 and has 3 transcripts. More than 300 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. 4 variants (2 nonsense, and 2 missense) that have been reported in approximately 4 probands in 2 publications (Venkatapuram VS et al., 2022; PMID: 34989141; Vissers LE et al., 2011; PMID:21549340). There is also a non-scorable publication that describes similar phenotypes of gPAPP deficiency but was not included in this curation (Nizon M et al., 2012; PMID:22887726). This gene-disease relationship is also supported by an animal models study (Frederick JP et al., 2008; PMID:18695242). In summary, there is moderate evidence to support the relationship between BPNT2 and Chondrodysplasia with joint dislocations GPAPP type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date XXX X, 2024 (SOP Version 10).

chondrodysplasia with joint dislocations, gPAPP typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013561

Submitter: PanelApp Australia

chondrodysplasia with joint dislocations, gPAPP typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013561

Submitter: Ambry Genetics

chondrodysplasia with joint dislocations, gPAPP typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013561

Submitter: Labcorp Genetics (formerly Invitae)

chondrodysplasia with joint dislocations, gPAPP typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013561

Submitter: Orphanet

chondrodysplasia with joint dislocations, gPAPP typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013561

Submitter: G2P

Clinical Genomic Database (CGD)

Chondrodysplasia with joint dislocations, GPAPP typeAR

Manifestation: Craniofacial; 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

Refs: 21549340; 22903787

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BPNT2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 108

not specifiedTotal: 56

Chondrodysplasia with joint dislocations, gPAPP typeTotal: 27

BPNT2-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017813.5. 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			5 clinvar	46 clinvar	1 clinvar	52
missense	2 clinvar	1 clinvar	83 clinvar	2 clinvar	1 clinvar	89
nonsense	2 clinvar					2
start loss						0
frameshift	4 clinvar	3 clinvar				7
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	8	4	91	48	2	153

Highest pathogenic variant AF is 0.000013631593

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017813.5	RefSeq	NP_060283.3	5	MANE Select
ENST00000262644.9	Ensembl	ENSP00000262644.4	5	MANE Select
ENST00000517461.1	Ensembl	ENSP00000430185.1	3	Standard
ENST00000520392.1	Ensembl	ENSP00000428617.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inositol phosphate metabolism - Homo sapiens (human)
Phosphatidylinositol signaling system - Homo sapiens (human)
Sulfur metabolism - Homo sapiens (human)
superpathway of D-<i>myo</i>-inositol (1,4,5)-trisphosphate metabolism
Phase II - Conjugation of compounds

Biological Process

skeletal system development
endochondral ossification
chondrocyte development
inositol biosynthetic process
post-embryonic development

Molecular Function

3'-nucleotidase activity
3'(2'),5'-bisphosphate nucleotidase activity
inositol monophosphate 1-phosphatase activity
metal ion binding
inositol monophosphate 3-phosphatase activity

Cellular Component

nucleus
Golgi apparatus
Golgi lumen
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262644
Coding exons: 5
Length: 35912
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.830	159	191	0.831	0.00000935	2312
Missense (PolyPhen)		55	73.524	0.74806		853
Synonymous	-1.79	97	77.0	1.26	0.00000399	747
Loss of Function	1.97	5	12.5	0.399	5.95e-7	156

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000057	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000098	0.000097	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in the formation of skeletal elements derived through endochondral ossification, possibly by clearing adenosine 3',5'-bisphosphate produced by Golgi sulfotransferases during glycosaminoglycan sulfation. {ECO:0000250}.;
Disease: DISEASE: Chondrodysplasia with joint dislocations, GPAPP type (CDP-GPAPP) [MIM:614078]: A condition consisting of congenital joint dislocations, chondrodysplasia with short stature, micrognathia and cleft palate, and a distinctive face. {ECO:0000269|PubMed:21549340}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.242
RVIS EVS: -0.32
RVIS percentile EVS: 31.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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