17-41813078-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_021939.4(FKBP10):c.44C>G(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,610,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P15P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

FKBP10
NM_021939.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0920

Publications

1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.011126041).

BP6

Variant 17-41813078-C-G is Benign according to our data. Variant chr17-41813078-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218789.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000651 (95/1458426) while in subpopulation AMR AF = 0.00213 (95/44702). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAdExome4. There are 34 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP10	NM_021939.4 link	c.44C>G	p.Pro15Arg	missense_variant	Exon 1 of 10	ENST00000321562.9	NP_068758.3	Q96AY3-1A0A024R1W3Q8NAG5Q658U4
FKBP10	XM_011525099.4 link	c.44C>G	p.Pro15Arg	missense_variant	Exon 1 of 11		XP_011523401.1
FKBP10	XM_011525100.3 link	c.-84C>G		5_prime_UTR_variant	Exon 1 of 10		XP_011523402.1
FKBP10	XM_047436515.1 link	c.-84C>G		5_prime_UTR_variant	Exon 1 of 9		XP_047292471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9 link	c.44C>G	p.Pro15Arg	missense_variant	Exon 1 of 10	1	NM_021939.4	ENSP00000317232.4		Q96AY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000348

AC:

AN:

241140

AF XY:

0.000257

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00239

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.0000651

AC:

AN:

1458426

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

725462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00213

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4538

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111690

Other (OTH)

AF:

0.00

AC:

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.000457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000159

ExAC

AF:

0.000257

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

May 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FKBP10 c.44C>G (p.Pro15Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00035 in 241140 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FKBP10 causing Osteogenesis Imperfecta (0.00035 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.44C>G in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 218789). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jul 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.44C>G (p.P15R) alteration is located in exon 1 (coding exon 1) of the FKBP10 gene. This alteration results from a C to G substitution at nucleotide position 44, causing the proline (P) at amino acid position 15 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L

PhyloP100

0.092

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.61

.;N

REVEL

Benign

0.045

Sift

Benign

0.056

.;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0

.;B

Vest4

0.17

MutPred

0.58

Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);

MVP

0.63

MPC

0.32

ClinPred

0.022

GERP RS

3.1

PromoterAI

-0.079

Neutral

(source)

Varity_R

0.048

gMVP

0.60

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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17-41813078-C-G

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