Variant 6-35620178-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004117.4(FKBP5):c.347C>A(p.Ala116Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

FKBP5
NM_004117.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.45

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FKBP5	NM_004117.4 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	4/11	ENST00000357266.9
FKBP5	NM_001145775.3 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	5/12
FKBP5	NM_001145776.2 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	4/11
FKBP5	NM_001145777.2 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	4/11	1	NM_004117.4	P1	Q13451-1
FKBP5	ENST00000536438.5 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	5/12	1		P1	Q13451-1
FKBP5	ENST00000539068.5 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	4/11	1		P1	Q13451-1
FKBP5	ENST00000542713.1 linkuse as main transcript	c.347C>A	p.Ala116Asp	missense_variant	4/7	2			Q13451-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

Apr 13, 2022

The c.347C>A (p.A116D) alteration is located in exon 5 (coding exon 3) of the FKBP5 gene. This alteration results from a C to A substitution at nucleotide position 347, causing the alanine (A) at amino acid position 116 to be replaced by an aspartic acid (D). 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

0.29

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T;T;.

Eigen

Benign

0.077

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;.;.;D

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.2

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.3

N;N;N;D

REVEL

Uncertain

0.45

Sift

Benign

0.070

T;T;T;T

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.15

B;B;B;.

Vest4

0.43

MutPred

0.45

Loss of catalytic residue at A116 (P = 0.0548);Loss of catalytic residue at A116 (P = 0.0548);Loss of catalytic residue at A116 (P = 0.0548);Loss of catalytic residue at A116 (P = 0.0548);

MVP

0.97

MPC

0.47

ClinPred

0.82

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.68

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over