rs143268242

chr7-30019098-C-Gchr7-30019098-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_017946.4(FKBP14):c.375G>C(p.Leu125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,581,300 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L125L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: FKBP14 NM_017946.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.776

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-30019098-C-G is Benign according to our data. Variant chr7-30019098-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 390831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30019098-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.776 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00148 (225/152174) while in subpopulation SAS AF= 0.00166 (8/4820). AF 95% confidence interval is 0.00129. There are 2 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP14	NM_017946.4	c.375G>C	p.Leu125=	synonymous_variant	3/4	ENST00000222803.10
FKBP14	XM_047420550.1	c.375G>C	p.Leu125=	synonymous_variant	3/4
FKBP14	NR_046478.2	n.661G>C		non_coding_transcript_exon_variant	4/5
FKBP14	NR_046479.2	n.417G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP14	ENST00000222803.10	c.375G>C	p.Leu125=	synonymous_variant	3/4	1	NM_017946.4	P1
FKBP14-AS1	ENST00000422239.6	n.680-6289C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152056 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00145 AC: 315 AN: 217214 Hom.: 4 AF XY: 0.00144 AC XY: 170 AN XY: 118314

Gnomad AFR exome AF: 0.000213

Gnomad AMR exome AF: 0.0000391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000658

Gnomad SAS exome AF: 0.000739

Gnomad FIN exome AF: 0.00734

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000966

GnomAD4 exome AF: 0.00108 AC: 1546 AN: 1429126 Hom.: 5 Cov.: 31 AF XY: 0.00107 AC XY: 763 AN XY: 710590

Gnomad4 AFR exome AF: 0.0000969

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.000801

Gnomad4 FIN exome AF: 0.00644

Gnomad4 NFE exome AF: 0.000996

Gnomad4 OTH exome AF: 0.000609

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152174 Hom.: 2 Cov.: 33 AF XY: 0.00179 AC XY: 133 AN XY: 74392

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00944

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000955 Hom.: 0

Bravo AF: 0.000559

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	FKBP14: BP4, BS2 -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	10
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs143268242; hg19: chr7-30058714;