12-48925056-A-C

Position:

chr12-48925056-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016594.3(FKBP11):c.185T>G(p.Ile62Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000781 in 1,535,864 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: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

FKBP11
NM_016594.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

Variant links:

Genes affected

FKBP11 (HGNC:18624): (FKBP prolyl isomerase 11) FKBP11 belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. The peptidyl-prolyl isomerase activity of FKBP proteins is inhibited by the immunosuppressant compounds FK506 and rapamycin (Rulten et al., 2006 [PubMed 16596453]).[supplied by OMIM, Mar 2008]

FKBP11 links:

ENSG00000272822 (HGNC:):

ENSG00000272822 links:

CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

CCDC65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP11	NM_016594.3 linkuse as main transcript	c.185T>G	p.Ile62Arg	missense_variant	2/6	ENST00000550765.6	NP_057678.1	Q9NYL4-1
FKBP11	NM_001143782.2 linkuse as main transcript	c.185T>G	p.Ile62Arg	missense_variant	2/6		NP_001137254.1	Q9NYL4-2
FKBP11	XM_047428939.1 linkuse as main transcript	c.156T>G	p.His52Gln	missense_variant	3/7		XP_047284895.1
FKBP11	XM_047428940.1 linkuse as main transcript	c.39T>G	p.His13Gln	missense_variant	2/6		XP_047284896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP11	ENST00000550765.6 linkuse as main transcript	c.185T>G	p.Ile62Arg	missense_variant	2/6	1	NM_016594.3	ENSP00000449751.1		Q9NYL4-1
ENSG00000272822	ENST00000398092.4 linkuse as main transcript	c.384+14599T>G		intron_variant		3		ENSP00000438507.1		F5H423

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

148826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249910

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000721

AC:

AN:

1387038

Hom.:

Cov.:

AF XY:

0.00000724

AC XY:

AN XY:

690378

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000466

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:

0.00000658

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000134

AC:

AN:

148826

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72560

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000298

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.185T>G (p.I62R) alteration is located in exon 2 (coding exon 2) of the FKBP11 gene. This alteration results from a T to G substitution at nucleotide position 185, causing the isoleucine (I) at amino acid position 62 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

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Uncertain

0.77

D;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.7

H;.;H

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.83

MutPred

0.76

Gain of catalytic residue at I62 (P = 0.0226);Gain of catalytic residue at I62 (P = 0.0226);Gain of catalytic residue at I62 (P = 0.0226);

MVP

0.99

MPC

0.93

ClinPred

0.99

GERP RS

4.4

Varity_R

0.93

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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