chr6-35587072-C-T

Position:

• chr6-35587072-C-T

Variant summary

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

The NM_004117.4(FKBP5):​c.802G>A​(p.Ala268Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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.802G>A	p.Ala268Thr	missense_variant	8/11	ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.802G>A	p.Ala268Thr	missense_variant	9/12		NP_001139247.1
FKBP5	NM_001145776.2	c.802G>A	p.Ala268Thr	missense_variant	8/11		NP_001139248.1
FKBP5	NM_001145777.2	c.711G>A	p.Arg237Arg	synonymous_variant	7/7		NP_001139249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.802G>A	p.Ala268Thr	missense_variant	8/11	1	NM_004117.4	ENSP00000349811.3
FKBP5	ENST00000536438.5	c.802G>A	p.Ala268Thr	missense_variant	9/12	1		ENSP00000444810.1
FKBP5	ENST00000539068.5	c.802G>A	p.Ala268Thr	missense_variant	8/11	1		ENSP00000441205.1
FKBP5	ENST00000542713.1	c.711G>A	p.Arg237Arg	synonymous_variant	7/7	2		ENSP00000442340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 24, 2024

The c.802G>A (p.A268T) alteration is located in exon 9 (coding exon 7) of the FKBP5 gene. This alteration results from a G to A substitution at nucleotide position 802, causing the alanine (A) at amino acid position 268 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	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;.;.
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.057	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.53
MutPred		0.28		Gain of disorder (P = 0.1329);Gain of disorder (P = 0.1329);Gain of disorder (P = 0.1329);
MVP		0.86
MPC		0.92
ClinPred		0.95	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.63
gMVP		0.72

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.

Other links and lift over

hg19: chr6-35554849;