6-35637156-A-C

Position:

• chr6-35637156-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004117.4(FKBP5):​c.108T>G​(p.Ile36Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,452,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FKBP5 NM_004117.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30380982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	3/11	ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	4/12		NP_001139247.1
FKBP5	NM_001145776.2	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	3/11		NP_001139248.1
FKBP5	NM_001145777.2	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	3/7		NP_001139249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	3/11	1	NM_004117.4	ENSP00000349811.3
FKBP5	ENST00000536438.5	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	4/12	1		ENSP00000444810.1
FKBP5	ENST00000539068.5	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	3/11	1		ENSP00000441205.1
FKBP5	ENST00000542713.1	c.108T>G	p.Ile36Met	missense_variant, splice_region_variant	3/7	2		ENSP00000442340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239660 Hom.: 0 AF XY: 0.00000771 AC XY: 1 AN XY: 129618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1452694 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 722406

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: 0.0000144

Gnomad4 OTH exome AF: 0.0000167

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 08, 2024

The c.108T>G (p.I36M) alteration is located in exon 4 (coding exon 2) of the FKBP5 gene. This alteration results from a T to G substitution at nucleotide position 108, causing the isoleucine (I) at amino acid position 36 to be replaced by a methionine (M). 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	0.090
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T;.;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	2.0	M;M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.39	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.95	P;P;P;.
Vest4		0.40
MutPred		0.37		Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);
MVP		0.53
MPC		0.31
ClinPred		0.39	T
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.16
gMVP		0.46

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: rs911743582; hg19: chr6-35604933;