6-35575888-T-C

Position:

• chr6-35575888-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004117.4(FKBP5):​c.1321A>G​(p.Lys441Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FKBP5 NM_004117.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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]

ACMG classification

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=0.079267055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4	c.1321A>G	p.Lys441Glu	missense_variant	11/11	ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.1321A>G	p.Lys441Glu	missense_variant	12/12		NP_001139247.1
FKBP5	NM_001145776.2	c.1321A>G	p.Lys441Glu	missense_variant	11/11		NP_001139248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.1321A>G	p.Lys441Glu	missense_variant	11/11	1	NM_004117.4	ENSP00000349811.3
FKBP5	ENST00000536438.5	c.1321A>G	p.Lys441Glu	missense_variant	12/12	1		ENSP00000444810.1
FKBP5	ENST00000539068.5	c.1321A>G	p.Lys441Glu	missense_variant	11/11	1		ENSP00000441205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.1321A>G (p.K441E) alteration is located in exon 12 (coding exon 10) of the FKBP5 gene. This alteration results from a A to G substitution at nucleotide position 1321, causing the lysine (K) at amino acid position 441 to be replaced by a glutamic acid (E). 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	0.070
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.61	T;.;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.63	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.043	B;B;B
Vest4		0.14
MutPred		0.35		Loss of ubiquitination at K441 (P = 0.0019);Loss of ubiquitination at K441 (P = 0.0019);Loss of ubiquitination at K441 (P = 0.0019);
MVP		0.95
MPC		0.43
ClinPred		0.063	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.32

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

Other links and lift over

dbSNP: rs573307937; hg19: chr6-35543665;