Genetic Variant FKBP14:p.His171Arg (chr7-30014859-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017946.4(FKBP14):c.512A>G(p.His171Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H171P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FKBP14
NM_017946.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Publications

0 publications found

Variant links:

Genes affected

FKBP14 (HGNC:18625): (FKBP prolyl isomerase 14) The protein encoded by this gene is a member of the FK506-binding protein family of peptidyl-prolyl cis-trans isomerases. The encoded protein is found in the lumen of the endoplasmic reticulum, where it is thought to accelerate protein folding. Defects in this gene are a cause of a type of Ehlers-Danlos syndrome (EDS). Both a protein-coding variant and noncoding variants are transcribed from this gene. [provided by RefSeq, Mar 2012]

FKBP14 links:

FKBP14-AS1 (HGNC:40990): (FKBP14 antisense RNA 1)

FKBP14-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP14	NM_017946.4 link	c.512A>G	p.His171Arg	missense_variant	Exon 4 of 4	ENST00000222803.10	NP_060416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP14	ENST00000222803.10 link	c.512A>G	p.His171Arg	missense_variant	Exon 4 of 4	1	NM_017946.4	ENSP00000222803.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446180

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32572

American (AMR)

AF:

0.00

AC:

AN:

39754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25410

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

82418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108114

Other (OTH)

AF:

0.00

AC:

AN:

59742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Jul 23, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.H171R variant (also known as c.512A>G), located in coding exon 4 of the FKBP14 gene, results from an A to G substitution at nucleotide position 512. The histidine at codon 171 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.1

PhyloP100

7.6

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.3

Sift

Benign

0.28

Sift4G

Benign

0.35

Vest4

0.72

ClinPred

0.92

GERP RS

5.9

Varity_R

0.49

gMVP

0.79

Mutation Taster

=24/76

disease causing

(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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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