6-35637134-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004117.4(FKBP5):c.130G>A(p.Glu44Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,608,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FKBP5
NM_004117.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.26

Variant links:

Genes affected

FKBP5 (HGNC:3721): (FKBP prolyl isomerase 5) The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature hetero-oligomeric progesterone receptor complexes along with the 90 kDa heat shock protein and P23 protein. This gene has been found to have multiple polyadenylation sites. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

FKBP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11408749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FKBP5	NM_004117.4 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	3/11	ENST00000357266.9
FKBP5	NM_001145775.3 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	4/12
FKBP5	NM_001145776.2 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	3/11
FKBP5	NM_001145777.2 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	3/11	1	NM_004117.4	P1	Q13451-1
FKBP5	ENST00000536438.5 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	4/12	1		P1	Q13451-1
FKBP5	ENST00000539068.5 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	3/11	1		P1	Q13451-1
FKBP5	ENST00000542713.1 linkuse as main transcript	c.130G>A	p.Glu44Lys	missense_variant	3/7	2			Q13451-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244276

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000309

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.130G>A (p.E44K) alteration is located in exon 4 (coding exon 2) of the FKBP5 gene. This alteration results from a G to A substitution at nucleotide position 130, causing the glutamic acid (E) at amino acid position 44 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;.;.;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.33

N;N;N;N

MutationTaster

Benign

1.0

D;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.29

T;T;T;T

Sift4G

Benign

0.40

T;T;T;T

Polyphen

0.13

B;B;B;.

Vest4

0.18

MutPred

0.47

Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);

MVP

1.0

MPC

0.35

ClinPred

0.26

GERP RS

4.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.20

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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