FKBP14

protein-coding

FKBP prolyl isomerase 14, the group of FKBP prolyl isomerases|EF-hand domain containing

Gene summary

The protein encoded by this gene is a member of the FK506-binding protein family of peptidyl-prolyl cis-trans isomerases. The encoded protein is found in the lumen of the endoplasmic reticulum, where it is thought to accelerate protein folding. Defects in this gene are a cause of a type of Ehlers-Danlos syndrome (EDS). Both a protein-coding variant and noncoding variants are transcribed from this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_017946.4

Inheritance

ClinVar variants

P:20U:137B:74

Top phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type, 2

gnomAD constraint

pLI —, LoF o/e 0.98

Max pathogenic AF

—

Genomic locus

chr7:30,010,587-30,026,702

External References & Databases

Ensembl (ENSG00000106080)

Transcript & Mutation Effects

hg38 • Region Span ~16.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ehlers-Danlos syndrome, kyphoscoliotic type, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013800

Submitter: PanelApp Australia

Ehlers-Danlos syndrome, kyphoscoliotic type, 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013800

Submitter: Ambry Genetics

Ehlers-Danlos syndrome, kyphoscoliotic type, 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013800

Submitter: Orphanet

Ehlers-Danlos syndrome, kyphoscoliotic type, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013800

Submitter: G2P

Ehlers-Danlos syndrome, kyphoscoliotic type, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013800

Submitter: Labcorp Genetics (formerly Invitae)

Ehlers-Danlos syndrome, kyphoscoliotic type, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013800

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Ehlers-Danlos syndrome, kyphoscoliotic type, 2AR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Genitourinary; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: Cardiovascular complications, including aortic rupture, have been described, and awareness and surveillance may allow rapid diagnosis and treatment, which may ameliorate morbidity and mortality

Refs: 22265013; 24773188

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FKBP14 variants in ClinVar

12 Conditions Cataloged

Ehlers-Danlos syndrome, kyphoscoliotic type, 2Total: 187

Cardiovascular phenotypeTotal: 145

not providedTotal: 48

not specifiedTotal: 33

FKBP14-related disorderTotal: 7

Ehlers-Danlos syndromeTotal: 7

FKBP14-related disordersTotal: 3

HypotoniaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017946.4. 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				65 clinvar	2 clinvar	67
missense			130 clinvar	7 clinvar		137
nonsense	3 clinvar	1 clinvar	2 clinvar			6
start loss						0
frameshift	6 clinvar	7 clinvar	1 clinvar			14
splice donor/acceptor (+/-2bp)		3 clinvar	4 clinvar			7
Total	9	11	137	72	2	231

Highest pathogenic variant AF is 0.0007022668

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017946.4	RefSeq	NP_060416.1	4	MANE Select
ENST00000222803.10	Ensembl	ENSP00000222803.5	4	MANE Select
ENST00000412494.1	Ensembl	ENSP00000403279.1	3	Standard
ENST00000419018.1	Ensembl	ENSP00000406270.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

XBP1(S) activates chaperone genes

Biological Process

protein peptidyl-prolyl isomerization
IRE1-mediated unfolded protein response

Molecular Function

peptidyl-prolyl cis-trans isomerase activity
calcium ion binding

Cellular Component

endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222803
Coding exons: 4
Length: 16098
Individuals with no LoFs: 125605
Homozygous LoFs: 0
Heterozygous LoFs: 143
Defined: 125748
p: 0.000569

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0939	105	108	0.975	0.00000479	1404
Missense (PolyPhen)		40	46.869	0.85344		607
Synonymous	0.782	33	39.2	0.841	0.00000189	371
Loss of Function	0.0702	9	9.23	0.975	4.60e-7	122

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00042	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00029	0.00028	rare
European (Non-Finnish)	0.0011	0.00098	notable
South Asian	0.00024	0.00023	rare
Other	0.00041	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: PPIase which accelerates the folding of proteins during protein synthesis. Has a preference for substrates containing 4- hydroxylproline modifications, including type III collagen. May also target type VI and type X collagens. {ECO:0000269|PubMed:24821723}.;
Disease: DISEASE: Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (EDSKSCL2) [MIM:614557]: A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSKSCL2 is an autosomal recessive form characterized by severe generalized hypotonia at birth, myopathy, early-onset progressive kyphoscoliosis, joint hypermobility without contractures, hyperelastic skin with follicular hyperkeratosis, easy bruising, and occasional abnormal scarring, sensorineural hearing impairment, and normal pyridinoline excretion in urine. {ECO:0000269|PubMed:22265013}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.751
RVIS EVS: -0.16
RVIS percentile EVS: 41.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.949

Gene Damage Prediction

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