chr6-35620218-A-G

Position:

• chr6-35620218-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004117.4(FKBP5):​c.307T>C​(p.Cys103Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: FKBP5 NM_004117.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4	c.307T>C	p.Cys103Arg	missense_variant	4/11	ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.307T>C	p.Cys103Arg	missense_variant	5/12		NP_001139247.1
FKBP5	NM_001145776.2	c.307T>C	p.Cys103Arg	missense_variant	4/11		NP_001139248.1
FKBP5	NM_001145777.2	c.307T>C	p.Cys103Arg	missense_variant	4/7		NP_001139249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.307T>C	p.Cys103Arg	missense_variant	4/11	1	NM_004117.4	ENSP00000349811.3
FKBP5	ENST00000536438.5	c.307T>C	p.Cys103Arg	missense_variant	5/12	1		ENSP00000444810.1
FKBP5	ENST00000539068.5	c.307T>C	p.Cys103Arg	missense_variant	4/11	1		ENSP00000441205.1
FKBP5	ENST00000542713.1	c.307T>C	p.Cys103Arg	missense_variant	4/7	2		ENSP00000442340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727240

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: 0.0000117

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

Nov 10, 2021

The c.307T>C (p.C103R) alteration is located in exon 5 (coding exon 3) of the FKBP5 gene. This alteration results from a T to C substitution at nucleotide position 307, causing the cysteine (C) at amino acid position 103 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	-0.30	N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.0	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.96
MutPred		0.62		Gain of MoRF binding (P = 0.0273);Gain of MoRF binding (P = 0.0273);Gain of MoRF binding (P = 0.0273);Gain of MoRF binding (P = 0.0273);
MVP		0.94
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.95

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: rs1261781238; hg19: chr6-35587995;