rs542489955
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_017946.4(FKBP14):c.362dupC(p.Glu122fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,574,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00072 ( 0 hom. )
Consequence
FKBP14
NM_017946.4 frameshift
NM_017946.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
FKBP14 (HGNC:18625): (FKBP prolyl isomerase 14) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.431 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-30019110-T-TG is Pathogenic according to our data. Variant chr7-30019110-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FKBP14 | NM_017946.4 | c.362dupC | p.Glu122fs | frameshift_variant | 3/4 | ENST00000222803.10 | NP_060416.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FKBP14 | ENST00000222803.10 | c.362dupC | p.Glu122fs | frameshift_variant | 3/4 | 1 | NM_017946.4 | ENSP00000222803.5 |
Frequencies
GnomAD3 genomes 0.000552 AC: 84AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000553 AC: 115AN: 207878Hom.: 0 AF XY: 0.000527 AC XY: 60AN XY: 113832
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GnomAD4 exome AF: 0.000718 AC: 1022AN: 1422610Hom.: 0 Cov.: 31 AF XY: 0.000693 AC XY: 490AN XY: 707318
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GnomAD4 genome 0.000552 AC: 84AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38AN XY: 74484
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:26Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type, 2 Pathogenic:12Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 10, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Research Centre for Medical Genetics, Federal State Budgetary Scientific Institution | Oct 23, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 20, 2020 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. This variant was detected in homozygous state. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 22, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple affected families as disease-causing [PMID 22265013, 27905128, 28617417, 24677762] - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetic Pathology Unit, University Of Rochester Medical Center | May 16, 2023 | This variant was identified in the homozygous state in a patient with kyphoscoliotic Ehlers-Danlos Syndrome (kEDS). This frameshift variant causes a premature termination codon and is predicted to result in loss-of-function. This variant is a known pathogenic variant that has been reported multiple times in patients with kEDS, as either homozygous or compound heterozygous. This variant has been submitted to ClinVar as pathogenic over twenty times. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2023 | Variant summary: FKBP14 c.362dupC (p.Glu122ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00055 in 207878 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKBP14 causing Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type. c.362dupC has been reported in the literature in multiple individuals affected with Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type (e.g., Colman_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36054293). 20 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Glu122Argfs*7) in the FKBP14 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKBP14 are known to be pathogenic (PMID: 22265013). This variant is present in population databases (rs542489955, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome (PMID: 22265013, 24677762, 27149304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279809). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 10, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 30, 2022 | - - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 27, 2019 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 30561154, 22265013, 28617417, 27905128).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24677762, 22265013, 33879512, 27149304, 27905128, 30561154, 31063316, 31132235, 31980526, 31589614, 33587123, 34426522, 34504686, 26582918, 28617417, 27535533) - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jul 20, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | FKBP14: PVS1, PM3, PM2:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 03, 2021 | PVS1, PM2, PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 22, 2024 | PP1, PP4, PM3_strong, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jun 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 09, 2017 | - - |
Hypotonia;C0699743:Congenital muscular dystrophy;C0749379:Thoracolumbar scoliosis;C1578482:Pes valgus;C1844820:Joint hypermobility Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 10, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2023 | The c.362dupC pathogenic mutation, located in coding exon 3 of the FKBP14 gene, results from a duplication of C at nucleotide position 362, causing a translational frameshift with a predicted alternate stop codon (p.E122Rfs*7). This mutation has been reported in multiple individuals with autosomal recessive Ehlers-Danlos syndrome, kyphoscoliotic type 2 (kEDS), including homozygous and compound heterozygous cases (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16;Murray ML et al. Am. J. Med. Genet. A, 2014 Jul;164A:1750-5; Dordoni C et al. Am. J. Med. Genet. A, 2016 08;170:2031-8; Bursztejn AC et al. Clin. Exp. Dermatol., 2017 Jan;42:64-67;Giunta C et al. Genet. Med., 2018 01;20:42-54). Fibroblast and mRNA studies from affected individuals showed absent and significantly reduced expression, respectively (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
FKBP14-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 18, 2024 | The FKBP14 c.362dupC variant is predicted to result in a frameshift and premature protein termination (p.Glu122Argfs*7). This variant has been reported in the homozygous state within individuals presenting with kyphoscoliotic Ehlers-Danlos syndrome (Giunta et al. 2018. PubMed ID: 28617417; Baumawnn et al. 2012. PubMed ID: 22265013; Bursztejn et al. 2017. PubMed ID: 27905128). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in FKBP14 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
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