6-35580221-C-T

Position:

• chr6-35580221-C-T

Variant summary

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

The NM_004117.4(FKBP5):​c.841G>A​(p.Gly281Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKBP5 NM_004117.4 missense, splice_region
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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	Protein	UniProt
FKBP5	NM_004117.4	c.841G>A	p.Gly281Arg	missense_variant, splice_region_variant	9/11	ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.841G>A	p.Gly281Arg	missense_variant, splice_region_variant	10/12		NP_001139247.1
FKBP5	NM_001145776.2	c.841G>A	p.Gly281Arg	missense_variant, splice_region_variant	9/11		NP_001139248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.841G>A	p.Gly281Arg	missense_variant, splice_region_variant	9/11	1	NM_004117.4	ENSP00000349811.3
FKBP5	ENST00000536438.5	c.841G>A	p.Gly281Arg	missense_variant, splice_region_variant	10/12	1		ENSP00000444810.1
FKBP5	ENST00000539068.5	c.841G>A	p.Gly281Arg	missense_variant, splice_region_variant	9/11	1		ENSP00000441205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Mar 28, 2024

The c.841G>A (p.G281R) alteration is located in exon 10 (coding exon 8) of the FKBP5 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the glycine (G) at amino acid position 281 to be replaced by an arginine (R). 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	0.16
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.15	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.93	P;P;P
Vest4		0.27
MutPred		0.40		Gain of MoRF binding (P = 0.0399);Gain of MoRF binding (P = 0.0399);Gain of MoRF binding (P = 0.0399);
MVP		0.81
MPC		0.40
ClinPred		0.52	D
GERP RS		5.9
Varity_R		0.099
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-35547998;