17-41818390-A-G

Position:

chr17-41818390-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/22 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 261438.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr17-41818390-A-G is described in Lovd as [Benign]. Variant chr17-41818390-A-G is described in Lovd as [Likely_benign].

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/exons	MANE
FKBP10	NM_021939.4 linkuse as main transcript	c.590A>G	p.Lys197Arg	missense_variant	4/10	ENST00000321562.9
FKBP10	XM_011525099.4 linkuse as main transcript	c.590A>G	p.Lys197Arg	missense_variant	4/11
FKBP10	XM_011525100.3 linkuse as main transcript	c.317A>G	p.Lys106Arg	missense_variant	3/10
FKBP10	XM_047436515.1 linkuse as main transcript	c.317A>G	p.Lys106Arg	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP10	ENST00000321562.9 linkuse as main transcript	c.590A>G	p.Lys197Arg	missense_variant	4/10	1	NM_021939.4	P1	Q96AY3-1
FKBP10	ENST00000706683.1 linkuse as main transcript	c.590A>G	p.Lys197Arg	missense_variant	4/8
FKBP10	ENST00000585664.5 linkuse as main transcript	c.410A>G	p.Lys137Arg	missense_variant	5/5	3
FKBP10	ENST00000489591.5 linkuse as main transcript	c.444A>G	p.Ter148=	stop_retained_variant, NMD_transcript_variant	3/9	2

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

GnomAD3 exomes

AF:

0.0483

AC:

12141

AN:

251362

Hom.:

425

AF XY:

0.0456

AC XY:

6192

AN XY:

135876

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 SAS exome

AF:

0.0286

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

Gnomad4 AFR exome

AF:

0.118

Gnomad4 AMR exome

AF:

0.0250

Gnomad4 ASJ exome

AF:

0.0290

Gnomad4 EAS exome

AF:

0.0994

Gnomad4 SAS exome

AF:

0.0267

Gnomad4 FIN exome

AF:

0.0601

Gnomad4 NFE exome

AF:

0.0386

Gnomad4 OTH exome

AF:

0.0461

GnomAD4 genome

AF:

0.0654

AC:

9964

AN:

152248

Hom.:

426

Cov.:

AF XY:

0.0657

AC XY:

4888

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.119

Gnomad4 AMR

AF:

0.0362

Gnomad4 ASJ

AF:

0.0308

Gnomad4 EAS

AF:

0.110

Gnomad4 SAS

AF:

0.0307

Gnomad4 FIN

AF:

0.0636

Gnomad4 NFE

AF:

0.0413

Gnomad4 OTH

AF:

0.0596

Alfa

AF:

0.0449

Hom.:

316

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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Osteogenesis imperfecta type 11

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Medical Molecular Genetics Department, National Research Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

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

MutationTaster

Benign

1.0

P;P

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

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

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