rs542489955

chr7-30019110-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017946.4(FKBP14):c.362_363insC(p.Glu122ArgfsTer7) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• 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]

FKBP14-AS1 (HGNC:40990): (FKBP14 antisense RNA 1)

ACMG classification

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. There are 4 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	UniProt
FKBP14	NM_017946.4	c.362_363insC	p.Glu122ArgfsTer7	frameshift_variant	3/4	ENST00000222803.10
FKBP14	XM_047420550.1	c.362_363insC	p.Glu122ArgfsTer7	frameshift_variant	3/4
FKBP14	NR_046478.2	n.648_649insC		non_coding_transcript_exon_variant	4/5
FKBP14	NR_046479.2	n.404_405insC		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP14	ENST00000222803.10	c.362_363insC	p.Glu122ArgfsTer7	frameshift_variant	3/4	1	NM_017946.4	P1
FKBP14-AS1	ENST00000422239.6	n.680-6272dup		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000553 AC: 115 AN: 207878 Hom.: 0 AF XY: 0.000527 AC XY: 60 AN XY: 113832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000428

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000408

GnomAD4 exome AF: 0.000718 AC: 1022 AN: 1422610 Hom.: 0 Cov.: 31 AF XY: 0.000693 AC XY: 490 AN XY: 707318

Gnomad4 AFR exome AF: 0.000197

Gnomad4 AMR exome AF: 0.000506

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.000415

Gnomad4 NFE exome AF: 0.000855

Gnomad4 OTH exome AF: 0.000579

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000666 Hom.: 0

Bravo AF: 0.000487

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 Pathogenic:11 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Research Centre for Medical Genetics, Federal State Budgetary Scientific Institution	Oct 23, 2020	- -
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. -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
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. -
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	Revvity Omics, Revvity	Apr 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 10, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 10, 2012	- -

not provided Pathogenic:11

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2017	- -
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, 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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 03, 2021	PVS1, PM2, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 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	Mayo Clinic Laboratories, Mayo Clinic	Oct 11, 2022	PP1, PP4, PM3_strong, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jun 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs542489955; hg19: chr7-30058726;