rs542254849

Positions:

chr7-30014872-CCTT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_017946.4(FKBP14):c.496_498del(p.Lys166del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00136 in 1,594,244 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 7 hom. )

Consequence

FKBP14
NM_017946.4 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.79

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_017946.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 7-30014872-CCTT-C is Benign according to our data. Variant chr7-30014872-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432169.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000986 (150/152192) while in subpopulation SAS AF= 0.00228 (11/4816). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FKBP14	NM_017946.4 linkuse as main transcript	c.496_498del	p.Lys166del	inframe_deletion	4/4	ENST00000222803.10	NP_060416.1
FKBP14	XM_047420550.1 linkuse as main transcript	c.477+4121_477+4123del		intron_variant			XP_047276506.1
FKBP14	NR_046478.2 linkuse as main transcript	n.782_784del		non_coding_transcript_exon_variant	5/5
FKBP14	NR_046479.2 linkuse as main transcript	n.538_540del		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP14	ENST00000222803.10 linkuse as main transcript	c.496_498del	p.Lys166del	inframe_deletion	4/4	1	NM_017946.4	ENSP00000222803	P1
FKBP14-AS1	ENST00000422239.6 linkuse as main transcript	n.679+6499_679+6501del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000986

AC:

150

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000998

AC:

229

AN:

229478

Hom.:

AF XY:

0.00116

AC XY:

145

AN XY:

124498

show subpopulations

Gnomad AFR exome

AF:

0.000314

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00255

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00197

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00161

GnomAD4 exome

AF:

0.00140

AC:

2015

AN:

1442052

Hom.:

AF XY:

0.00143

AC XY:

1027

AN XY:

717198

show subpopulations

Gnomad4 AFR exome

AF:

0.000247

Gnomad4 AMR exome

AF:

0.000463

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.000360

Gnomad4 NFE exome

AF:

0.00153

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.000986

AC:

150

AN:

152192

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00153

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	FKBP14: PM4:Supporting, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	See Variant Classification Assertion Criteria. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.496_498delAAG variant (also known as p.K166del), located in coding exon 4 of the FKBP14 gene, results from an in-frame AAG deletion at nucleotide positions 496 to 498. This results in the in-frame deletion of a lysine at codon 166. This variant was reported in one heterozygous individual from a cervical insufficiency cohort (Volozonoka L et al. PLoS One, 2020 Mar;15:e0230771). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 31, 2022

- -

Ehlers-Danlos syndrome, kyphoscoliotic type, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

FKBP14-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over