Genetic Variant FKBP8:p.Val398Ile (chr19-18532219-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_012181.5(FKBP8):c.1192G>A(p.Val398Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,610,098 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

FKBP8
NM_012181.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.35

Variant links:

Genes affected

FKBP8 (HGNC:3724): (FKBP prolyl isomerase 8) 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. Unlike the other members of the family, this encoded protein does not seem to have PPIase/rotamase activity. It may have a role in neurons associated with memory function. [provided by RefSeq, Jul 2008]

FKBP8 links:

ENSG00000268938 (HGNC:):

ENSG00000268938 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12824506).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP8	NM_012181.5 link	c.1192G>A	p.Val398Ile	missense_variant	Exon 9 of 9	ENST00000608443.6	NP_036313.3	Q14318-2
FKBP8	NM_001308373.2 link	c.1189G>A	p.Val397Ile	missense_variant	Exon 9 of 9		NP_001295302.1	Q14318-1A0A024R7P2B2R8G6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP8	ENST00000608443.6 link	c.1192G>A	p.Val398Ile	missense_variant	Exon 9 of 9	1	NM_012181.5	ENSP00000476767.1		Q14318-2

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

242536

Hom.:

AF XY:

0.0000382

AC XY:

AN XY:

131056

show subpopulations

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:

0.0000549

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1458088

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724870

show subpopulations

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:

0.0000333

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000724

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1192G>A (p.V398I) alteration is located in exon 9 (coding exon 8) of the FKBP8 gene. This alteration results from a G to A substitution at nucleotide position 1192, causing the valine (V) at amino acid position 398 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

.;.;T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

.;D;.;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;.;L;L;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.28

.;N;.;.;.

REVEL

Benign

0.054

Sift

Benign

0.41

.;T;.;.;.

Sift4G

Benign

0.31

T;.;T;T;T

Polyphen

0.0080

B;.;B;B;B

Vest4

0.16

MutPred

0.33

.;.;Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);.;

MVP

0.43

MPC

0.54

ClinPred

0.14

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over