chr7-30014872-CCTT-C

Variant names:

• chr7-30014872-CCTT-C
• rs542254849
• NM_017946.4:c.496_498delAAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_017946.4(FKBP14):​c.496_498delAAG​(p.Lys166del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 5.79

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

Our verdict: Benign. The variant received -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: {Uncertain_significance=2, Likely_benign=4}.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP14	NM_017946.4	c.496_498delAAG	p.Lys166del	conservative_inframe_deletion	Exon 4 of 4	ENST00000222803.10	NP_060416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP14	ENST00000222803.10	c.496_498delAAG	p.Lys166del	conservative_inframe_deletion	Exon 4 of 4	1	NM_017946.4	ENSP00000222803.5

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152074 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000998 AC: 229 AN: 229478 AF XY: 0.00116

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 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.: 7 AF XY: 0.00143 AC XY: 1027 AN XY: 717198

Gnomad4 AFR exome AF: 0.000247 AC: 8 AN: 32422

Gnomad4 AMR exome AF: 0.000463 AC: 18 AN: 38868

Gnomad4 ASJ exome AF: 0.00214 AC: 54 AN: 25188

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39414

Gnomad4 SAS exome AF: 0.00177 AC: 145 AN: 81736

Gnomad4 FIN exome AF: 0.000360 AC: 19 AN: 52732

Gnomad4 NFE exome AF: 0.00153 AC: 1692 AN: 1106466

Gnomad4 Remaining exome AF: 0.00123 AC: 73 AN: 59556

GnomAD4 genome AF: 0.000986 AC: 150 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74414

Gnomad4 AFR AF: 0.000385 AC: 0.000385375 AN: 0.000385375

Gnomad4 AMR AF: 0.000327 AC: 0.000327139 AN: 0.000327139

Gnomad4 ASJ AF: 0.00374 AC: 0.00374424 AN: 0.00374424

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00228 AC: 0.00228405 AN: 0.00228405

Gnomad4 FIN AF: 0.000189 AC: 0.000188786 AN: 0.000188786

Gnomad4 NFE AF: 0.00147 AC: 0.00147059 AN: 0.00147059

Gnomad4 OTH AF: 0.000947 AC: 0.00094697 AN: 0.00094697

Alfa AF: 0.00153 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jan 17, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FKBP14: PM4:Supporting, BS2 -

Jun 01, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Uncertain:1

Apr 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 31, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FKBP14-related disorder Benign:1

Apr 12, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
Mutation Taster		=48/52	disease causing

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: rs542254849; hg19: chr7-30054488; COSMIC: COSV106093285;