6-35575942-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004117.4(FKBP5):c.1267G>A(p.Glu423Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,596,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

FKBP5
NM_004117.4 missense, splice_region

Scores

Splicing: ADA: 0.006815

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.43

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:

LOC101929309 (HGNC:):

LOC101929309 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057566047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FKBP5	NM_004117.4 linkuse as main transcript	c.1267G>A	p.Glu423Lys	missense_variant, splice_region_variant	11/11	ENST00000357266.9
LOC101929309	XR_242006.4 linkuse as main transcript	n.182-17088C>T		intron_variant, non_coding_transcript_variant
FKBP5	NM_001145775.3 linkuse as main transcript	c.1267G>A	p.Glu423Lys	missense_variant, splice_region_variant	12/12
FKBP5	NM_001145776.2 linkuse as main transcript	c.1267G>A	p.Glu423Lys	missense_variant, splice_region_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9 linkuse as main transcript	c.1267G>A	p.Glu423Lys	missense_variant, splice_region_variant	11/11	1	NM_004117.4	P1	Q13451-1
FKBP5	ENST00000536438.5 linkuse as main transcript	c.1267G>A	p.Glu423Lys	missense_variant, splice_region_variant	12/12	1		P1	Q13451-1
FKBP5	ENST00000539068.5 linkuse as main transcript	c.1267G>A	p.Glu423Lys	missense_variant, splice_region_variant	11/11	1		P1	Q13451-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

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:

0.000957

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249308

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134938

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

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:

0.000326

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1444052

Hom.:

Cov.:

AF XY:

0.00000973

AC XY:

AN XY:

719448

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

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:

0.0000502

GnomAD4 genome

AF:

0.000191

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00177

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:

0.000947

Bravo

AF:

0.000363

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

Dec 15, 2023

The c.1267G>A (p.E423K) alteration is located in exon 12 (coding exon 10) of the FKBP5 gene. This alteration results from a G to A substitution at nucleotide position 1267, causing the glutamic acid (E) at amino acid position 423 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

0.097

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Uncertain

-0.010

Cadd

Benign

Dann

Benign

0.89

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

-0.095

Eigen_PC

Benign

0.021

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;.;.

M_CAP

Benign

0.039

MetaRNN

Benign

0.058

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.53

N;N;N

MutationTaster

Benign

0.97

D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

0.61

N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.83

T;T;T

Sift4G

Benign

0.95

T;T;T

Polyphen

0.81

P;P;P

Vest4

0.20

MVP

0.97

MPC

0.35

ClinPred

0.053

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.083

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0068

dbscSNV1_RF

Benign

0.29

SpliceAI score (max)

0.12

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