FKBP10

protein-coding

FKBP prolyl isomerase 10, the group of EF-hand domain containing|FKBP prolyl isomerases

Gene summary

The protein encoded by this gene belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) family. This protein localizes to the endoplasmic reticulum and acts as a molecular chaperone. Alternatively spliced variants encoding different isoforms have been reported, but their biological validity has not been determined.[provided by RefSeq, Nov 2009]

MANE transcript

NM_021939.4

Inheritance

AD, AR

ClinVar variants

P:81U:199B:217

Top phenotype

Osteogenesis imperfecta, type XI; Bruck syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr17:41,812,680-41,823,213

External References & Databases

Ensembl (ENSG00000141756)

Transcript & Mutation Effects

hg38 • Region Span ~10.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteogenesis imperfecta type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009804

Submitter: Orphanet

Bruck syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017195

Submitter: Orphanet

osteogenesis imperfecta type 4SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008148

Submitter: Orphanet

osteogenesis imperfectaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019019

Submitter: PanelApp Australia

osteogenesis imperfecta type 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012592

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Bruck syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009806

Submitter: Labcorp Genetics (formerly Invitae)

arthrogryposis-like syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015241

Submitter: Orphanet

osteogenesis imperfecta type 11DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012592

Submitter: Illumina

The FKBP10 gene is located on chromosome 17 at 17q21.2 and encodes the FKBP prolyl isomerase 10 protein, which is a member of the immunophilins group of proteins. FKBP prolyl isomerase 10 protein has peptidyl prolyl cis-trans isomerase activity (PPIase) that accelerates protein folding, and it may also enable collagen folding by acting as a collagen chaperon. FKBP10 was first reported in relation to autosomal recessive osteogenesis imperfecta with or without joint contractures in 2010 (20362275: Alanay et al. (2010). At least six unique loss-of-function variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands from four publications (20362275: Alanay et al. 2010; 21567934: Shaheen et al. 2011; 20839288: Kelley et al. 2011; 27762305: Xu et al. 2017). Segregation was noted in four families but with insufficient evidence to score. More genetic evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by expression studies and animal models. In summary, FKBP10 is definitively associated with autosomal recessive osteogenesis imperfecta with or without joint contractures. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities (Marini et al. 2014): Bruck syndrome 1 (MIM:259450) and Osteogenesis imperfecta, type XI (MIM:610968).

osteogenesis imperfecta type 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012592

Submitter: Labcorp Genetics (formerly Invitae)

Bruck syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009806

Submitter: G2P

Clinical Genomic Database (CGD)

Osteogenesis imperfecta, type XI; Bruck syndrome 1AR

Manifestation: Dental; 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: Bisphosphonates may reduce fracture frequency, but it is unclear if early (genomic) diagnosis would be additionally beneficial

Refs: 20362275; 20696291; 20839288; 21567934

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FKBP10 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 514

Inborn genetic diseasesTotal: 103

Osteogenesis imperfecta type 11Total: 95

not specifiedTotal: 65

Bruck syndrome 1Total: 37

Osteogenesis imperfectaTotal: 30

FKBP10-related disorderTotal: 25

FKBP10-related disordersTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021939.4. 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	203 clinvar	3 clinvar	209
missense		10 clinvar	195 clinvar	11 clinvar		216
nonsense	8 clinvar	3 clinvar				11
start loss	1 clinvar	1 clinvar				2
frameshift	29 clinvar	16 clinvar				45
splice donor/acceptor (+/-2bp)	3 clinvar	10 clinvar	1 clinvar			14
Total	41	40	199	214	3	497

Highest pathogenic variant AF is 0.00009669921

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021939.4	RefSeq	NP_068758.3	10	MANE Select
ENST00000321562.9	Ensembl	ENSP00000317232.4	10	MANE Select
ENST00000429461.5	Ensembl	ENSP00000408232.1	3	Standard
ENST00000455106.1	Ensembl	ENSP00000416822.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein peptidyl-prolyl isomerization

Molecular Function

peptidyl-prolyl cis-trans isomerase activity
calcium ion binding
FK506 binding

Cellular Component

endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000321562
Coding exons: 10
Length: 10534
Individuals with no LoFs: 125670
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125748
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.713	322	360	0.894	0.0000239	3769
Missense (PolyPhen)		128	158.51	0.80752		1677
Synonymous	-1.04	177	160	1.10	0.0000115	1207
Loss of Function	2.13	13	24.3	0.535	0.00000139	259

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00033	0.00032	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: PPIases accelerate the folding of proteins during protein synthesis.;
Disease: DISEASE: Osteogenesis imperfecta 11 (OI11) [MIM:610968]: A form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI11 is an autosomal recessive form. {ECO:0000269|PubMed:20362275, ECO:0000269|PubMed:20839288, ECO:0000269|PubMed:22949511}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bruck syndrome 1 (BRKS1) [MIM:259450]: A disease characterized by generalized osteopenia, congenital joint contractures, fragile bones with onset of fractures in infancy or early childhood, short stature, severe limb deformity, progressive scoliosis, and pterygia. {ECO:0000269|PubMed:20839288, ECO:0000269|PubMed:22949511}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.337
RVIS EVS: -0.75
RVIS percentile EVS: 13.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.722

Gene Damage Prediction

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