Variant 6-35597399-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004117.4(FKBP5):c.514C>G(p.Leu172Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FKBP5
NM_004117.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.09

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4 link	c.514C>G	p.Leu172Val	missense_variant	6/11	ENST00000357266.9	NP_004108.1	Q13451-1Q2TA84
FKBP5	NM_001145775.3 link	c.514C>G	p.Leu172Val	missense_variant	7/12		NP_001139247.1	Q13451-1
FKBP5	NM_001145776.2 link	c.514C>G	p.Leu172Val	missense_variant	6/11		NP_001139248.1	Q13451-1
FKBP5	NM_001145777.2 link	c.514C>G	p.Leu172Val	missense_variant	6/7		NP_001139249.1	Q13451-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FKBP5	ENST00000357266.9 link	c.514C>G	p.Leu172Val	missense_variant	6/11	1	NM_004117.4	ENSP00000349811.3	Q13451-1
FKBP5	ENST00000536438.5 link	c.514C>G	p.Leu172Val	missense_variant	7/12	1		ENSP00000444810.1	Q13451-1
FKBP5	ENST00000539068.5 link	c.514C>G	p.Leu172Val	missense_variant	6/11	1		ENSP00000441205.1	Q13451-1
FKBP5	ENST00000542713.1 link	c.514C>G	p.Leu172Val	missense_variant	6/7	2		ENSP00000442340.1	Q13451-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250268

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461120

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726890

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

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

Aug 26, 2024

The c.514C>G (p.L172V) alteration is located in exon 7 (coding exon 5) of the FKBP5 gene. This alteration results from a C to G substitution at nucleotide position 514, causing the leucine (L) at amino acid position 172 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;.;.;D

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.1

M;M;M;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.061

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.98

D;D;D;.

Vest4

0.67

MutPred

0.63

Gain of methylation at R175 (P = 0.1333);Gain of methylation at R175 (P = 0.1333);Gain of methylation at R175 (P = 0.1333);Gain of methylation at R175 (P = 0.1333);

MVP

0.92

MPC

0.39

ClinPred

0.56

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.63

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