rs761395463

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I62V) has been classified 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 was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
FKBP11	NM_016594.3 link	c.185T>G	p.Ile62Arg	missense_variant	Exon 2 of 6	ENST00000550765.6	NP_057678.1	Q9NYL4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP11	ENST00000550765.6 link	c.185T>G	p.Ile62Arg	missense_variant	Exon 2 of 6	1	NM_016594.3	ENSP00000449751.1		Q9NYL4-1
ENSG00000272822	ENST00000398092.4 link	c.384+14599T>G		intron_variant	Intron 4 of 4	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

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249910

AF XY:

0.0000222

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 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

African (AFR)

AF:

0.00

AC:

AN:

31570

American (AMR)

AF:

0.0000466

AC:

AN:

42882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23930

East Asian (EAS)

AF:

0.00

AC:

AN:

34384

South Asian (SAS)

AF:

0.00

AC:

AN:

85404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

0.00000658

AC:

AN:

1063630

Other (OTH)

AF:

0.0000179

AC:

AN:

55968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000134

AC:

AN:

148826

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72560

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40748

American (AMR)

AF:

0.00

AC:

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

4898

South Asian (SAS)

AF:

0.00

AC:

AN:

4576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

67080

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Aug 23, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.9

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

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.93

gMVP

0.97

Mutation Taster

=66/34

polymorphism

(source)

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

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rs761395463

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over