6-35619125-G-A

Variant summary

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

The NM_004117.4(FKBP5):c.479C>T(p.Ser160Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,461,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FKBP5 NM_004117.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP5	NM_004117.4	c.479C>T	p.Ser160Leu	missense_variant	5/11	ENST00000357266.9
FKBP5	NM_001145775.3	c.479C>T	p.Ser160Leu	missense_variant	6/12
FKBP5	NM_001145776.2	c.479C>T	p.Ser160Leu	missense_variant	5/11
FKBP5	NM_001145777.2	c.479C>T	p.Ser160Leu	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9	c.479C>T	p.Ser160Leu	missense_variant	5/11	1	NM_004117.4	P1
FKBP5	ENST00000536438.5	c.479C>T	p.Ser160Leu	missense_variant	6/12	1		P1
FKBP5	ENST00000539068.5	c.479C>T	p.Ser160Leu	missense_variant	5/11	1		P1
FKBP5	ENST00000542713.1	c.479C>T	p.Ser160Leu	missense_variant	5/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461064 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726934

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 10, 2023

The c.479C>T (p.S160L) alteration is located in exon 6 (coding exon 4) of the FKBP5 gene. This alteration results from a C to T substitution at nucleotide position 479, causing the serine (S) at amino acid position 160 to be replaced by a leucine (L). 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	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;.;T
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.068	T;T;T;D
Sift4G	Benign	0.22	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.51
MutPred		0.50		Loss of glycosylation at S160 (P = 0.0459);Loss of glycosylation at S160 (P = 0.0459);Loss of glycosylation at S160 (P = 0.0459);Loss of glycosylation at S160 (P = 0.0459);
MVP		0.98
MPC		0.34
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.47

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: rs1763748379; hg19: chr6-35586902;