rs34764749

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_021939.4(FKBP10):c.590A>G(p.Lys197Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 1,614,136 control chromosomes in the GnomAD database, including 2,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K197K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 426 hom., cov: 31)

Exomes 𝑓: 0.042 ( 1597 hom. )

Consequence

FKBP10
NM_021939.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.25

Publications

23 publications found

Variant links:

Genes affected

FKBP10 (HGNC:18169): (FKBP prolyl isomerase 10) The protein encoded by this gene belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) family. This protein localizes to the endoplasmic reticulum and acts as a molecular chaperone. Alternatively spliced variants encoding different isoforms have been reported, but their biological validity has not been determined.[provided by RefSeq, Nov 2009]

FKBP10 Gene-Disease associations (from GenCC):

Bruck syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
osteogenesis imperfecta type 11
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Illumina
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arthrogryposis-like syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Bruck syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FKBP10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 17-41818390-A-G is Benign according to our data. Variant chr17-41818390-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261438.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP10	NM_021939.4 link	c.590A>G	p.Lys197Arg	missense_variant	Exon 4 of 10	ENST00000321562.9	NP_068758.3	Q96AY3-1A0A024R1W3Q8NAG5Q658U4
FKBP10	XM_011525099.4 link	c.590A>G	p.Lys197Arg	missense_variant	Exon 4 of 11		XP_011523401.1
FKBP10	XM_011525100.3 link	c.317A>G	p.Lys106Arg	missense_variant	Exon 3 of 10		XP_011523402.1
FKBP10	XM_047436515.1 link	c.317A>G	p.Lys106Arg	missense_variant	Exon 3 of 9		XP_047292471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9 link	c.590A>G	p.Lys197Arg	missense_variant	Exon 4 of 10	1	NM_021939.4	ENSP00000317232.4		Q96AY3-1

Frequencies

GnomAD3 genomes

AF:

0.0652

AC:

9924

AN:

152130

Hom.:

416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0364

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0413

Gnomad OTH

AF:

0.0593

GnomAD2 exomes

AF:

0.0483

AC:

12141

AN:

251362

AF XY:

0.0456

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0274

Gnomad EAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.0643

Gnomad NFE exome

AF:

0.0397

Gnomad OTH exome

AF:

0.0406

GnomAD4 exome

AF:

0.0418

AC:

61179

AN:

1461888

Hom.:

1597

Cov.:

AF XY:

0.0410

AC XY:

29835

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.118

AC:

3940

AN:

33480

American (AMR)

AF:

0.0250

AC:

1120

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0290

AC:

759

AN:

26136

East Asian (EAS)

AF:

0.0994

AC:

3945

AN:

39698

South Asian (SAS)

AF:

0.0267

AC:

2299

AN:

86258

European-Finnish (FIN)

AF:

0.0601

AC:

3208

AN:

53418

Middle Eastern (MID)

AF:

0.0250

AC:

144

AN:

5768

European-Non Finnish (NFE)

AF:

0.0386

AC:

42979

AN:

1112010

Other (OTH)

AF:

0.0461

AC:

2785

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

4127

8254

12380

16507

20634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1722

3444

5166

6888

8610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0654

AC:

9964

AN:

152248

Hom.:

426

Cov.:

AF XY:

0.0657

AC XY:

4888

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.119

AC:

4922

AN:

41532

American (AMR)

AF:

0.0362

AC:

553

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

107

AN:

3470

East Asian (EAS)

AF:

0.110

AC:

570

AN:

5172

South Asian (SAS)

AF:

0.0307

AC:

148

AN:

4828

European-Finnish (FIN)

AF:

0.0636

AC:

675

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0413

AC:

2810

AN:

68020

Other (OTH)

AF:

0.0596

AC:

126

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

481

962

1444

1925

2406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0455

Hom.:

669

Bravo

AF:

0.0660

TwinsUK

AF:

0.0364

AC:

135

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.110

AC:

484

ESP6500EA

AF:

0.0391

AC:

336

ExAC

AF:

0.0490

AC:

5944

Asia WGS

AF:

0.0770

AC:

266

AN:

3478

EpiCase

AF:

0.0360

EpiControl

AF:

0.0392

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Sep 13, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta type 11

Uncertain:1Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Medical Molecular Genetics Department, National Research Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.025

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.9

.;N

PhyloP100

3.3

PrimateAI

Benign

0.30

PROVEAN

Benign

1.4

.;N

REVEL

Benign

0.073

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.062

MPC

0.21

ClinPred

0.0066

GERP RS

1.4

Varity_R

0.068

gMVP

0.36

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over