6-35637157-A-G

Position:

chr6-35637157-A-G

Variant summary

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

The NM_004117.4(FKBP5):c.107T>C(p.Ile36Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,605,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 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 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

FKBP5
NM_004117.4 missense, splice_region

Scores

Splicing: ADA: 0.2175

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.29

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 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=0.028061569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	3/11	ENST00000357266.9	NP_004108.1	Q13451-1Q2TA84
FKBP5	NM_001145775.3 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	4/12		NP_001139247.1	Q13451-1
FKBP5	NM_001145776.2 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	3/11		NP_001139248.1	Q13451-1
FKBP5	NM_001145777.2 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	3/7		NP_001139249.1	Q13451-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FKBP5	ENST00000357266.9 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	3/11	1	NM_004117.4	ENSP00000349811.3	Q13451-1
FKBP5	ENST00000536438.5 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	4/12	1		ENSP00000444810.1	Q13451-1
FKBP5	ENST00000539068.5 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	3/11	1		ENSP00000441205.1	Q13451-1
FKBP5	ENST00000542713.1 linkuse as main transcript	c.107T>C	p.Ile36Thr	missense_variant, splice_region_variant	3/7	2		ENSP00000442340.1	Q13451-2

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000427

AC:

103

AN:

241300

Hom.:

AF XY:

0.000422

AC XY:

AN XY:

130444

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.000928

Gnomad ASJ exome

AF:

0.00244

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.000509

GnomAD4 exome

AF:

0.000202

AC:

293

AN:

1453170

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

156

AN XY:

722666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00266

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00105

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.000383

GnomAD4 genome

AF:

0.000361

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000266

Hom.:

Bravo

AF:

0.000620

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000237

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

Nov 21, 2023

The c.107T>C (p.I36T) alteration is located in exon 4 (coding exon 2) of the FKBP5 gene. This alteration results from a T to C substitution at nucleotide position 107, causing the isoleucine (I) at amino acid position 36 to be replaced by a threonine (T). 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

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;.;.;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.028

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

M;M;M;M

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.88

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.56

T;T;T;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.86

P;P;P;.

Vest4

0.58

MVP

0.66

MPC

0.39

ClinPred

0.79

GERP RS

5.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.24

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.22

dbscSNV1_RF

Benign

0.35

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