NM_021939.4:c.16C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021939.4(FKBP10):c.16C>G(p.Pro6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,457,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FKBP10
NM_021939.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057593256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP10	NM_021939.4 link	c.16C>G	p.Pro6Ala	missense_variant	Exon 1 of 10	ENST00000321562.9	NP_068758.3	Q96AY3-1A0A024R1W3Q8NAG5Q658U4
FKBP10	XM_011525099.4 link	c.16C>G	p.Pro6Ala	missense_variant	Exon 1 of 11		XP_011523401.1
FKBP10	XM_011525100.3 link	c.-112C>G		5_prime_UTR_variant	Exon 1 of 10		XP_011523402.1
FKBP10	XM_047436515.1 link	c.-112C>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.16C>G	p.Pro6Ala	missense_variant	Exon 1 of 10	1	NM_021939.4	ENSP00000317232.4		Q96AY3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000840

AC:

AN:

238018

AF XY:

0.00000763

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1457856

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

725216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4230

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111622

Other (OTH)

AF:

0.0000166

AC:

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 6 of the FKBP10 protein (p.Pro6Ala). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FKBP10-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.9

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0092

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N

PhyloP100

-1.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.27

.;N

REVEL

Benign

0.027

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.13

MutPred

0.25

Loss of glycosylation at P6 (P = 0.0118);Loss of glycosylation at P6 (P = 0.0118);

MVP

0.51

MPC

0.25

ClinPred

0.020

GERP RS

0.30

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.018

gMVP

0.23

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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NM_021939.4:c.16C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over