rs542489955

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_017946.4(FKBP14):c.362dupC(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 (★★). ClinVar reports functional evidence for this variant: "SCV002618108: Fibroblast and mRNA studies from affected individuals showed absent and significantly reduced expression, respectively (Baumann M et al. Am. J. Hum. Genet., 2012 Feb" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

FKBP14
NM_017946.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30O:2

Conservation

PhyloP100: 9.60

Publications

24 publications found

Variant links:

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 links:

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

FKBP14-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002618108: 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).

PP5

Variant 7-30019110-T-TG is Pathogenic according to our data. Variant chr7-30019110-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FKBP14	NM_017946.4	MANE Select	c.362dupC	p.Glu122ArgfsTer7	frameshift	Exon 3 of 4	NP_060416.1	Q9NWM8
FKBP14	NR_046478.2		n.648dupC		non_coding_transcript_exon	Exon 4 of 5
FKBP14	NR_046479.2		n.404dupC		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FKBP14	ENST00000222803.10	TSL:1 MANE Select	c.362dupC	p.Glu122ArgfsTer7	frameshift	Exon 3 of 4	ENSP00000222803.5	Q9NWM8
FKBP14	ENST00000419018.1	TSL:1	n.*9dupC		non_coding_transcript_exon	Exon 2 of 3	ENSP00000406270.1	F8WBZ0
FKBP14	ENST00000419018.1	TSL:1	n.*9dupC		3_prime_UTR	Exon 2 of 3	ENSP00000406270.1	F8WBZ0

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000553

AC:

115

AN:

207878

AF XY:

0.000527

show subpopulations

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 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.:

Cov.:

AF XY:

0.000693

AC XY:

490

AN XY:

707318

show subpopulations

African (AFR)

AF:

0.000197

AC:

AN:

30412

American (AMR)

AF:

0.000506

AC:

AN:

33624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25006

East Asian (EAS)

AF:

0.00

AC:

AN:

36942

South Asian (SAS)

AF:

0.0000253

AC:

AN:

78952

European-Finnish (FIN)

AF:

0.000415

AC:

AN:

53012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000855

AC:

941

AN:

1100222

Other (OTH)

AF:

0.000579

AC:

AN:

58754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000552

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41568

American (AMR)

AF:

0.00111

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000666

Hom.:

Bravo

AF:

0.000487

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (16)

not provided (12)

Cardiovascular phenotype (2)

FKBP14-related disorder (1)

Hypotonia;C0699743:Congenital muscular dystrophy;C0749379:Thoracolumbar scoliosis;C1578482:Pes valgus;C1844820:Joint hypermobility (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.6

Mutation Taster

=14/186

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over