Genetic Variant NM_004117.4:c.-19-8934C>T (chr6-35651777-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004117.4(FKBP5):c.-19-8934C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 218,480 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.043 ( 175 hom., cov: 32)

Exomes 𝑓: 0.023 ( 25 hom. )

Consequence

FKBP5
NM_004117.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.507

Publications

7 publications found

Variant links:

Genes affected

FKBP5 (HGNC:3721): (FKBP prolyl isomerase 5) The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature hetero-oligomeric progesterone receptor complexes along with the 90 kDa heat shock protein and P23 protein. This gene has been found to have multiple polyadenylation sites. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

FKBP5 links:

ENSG00000287458 (HGNC:):

ENSG00000287458 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP5	NM_004117.4 link	c.-19-8934C>T		intron_variant	Intron 1 of 10	ENST00000357266.9	NP_004108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9 link	c.-19-8934C>T		intron_variant	Intron 1 of 10	1	NM_004117.4	ENSP00000349811.3

Frequencies

GnomAD3 genomes

AF:

0.0426

AC:

6478

AN:

152038

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0794

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0487

Gnomad ASJ

AF:

0.0563

Gnomad EAS

AF:

0.0555

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0241

Gnomad OTH

AF:

0.0421

GnomAD4 exome

AF:

0.0229

AC:

1516

AN:

66324

Hom.:

Cov.:

AF XY:

0.0220

AC XY:

767

AN XY:

34802

show subpopulations

African (AFR)

AF:

0.0843

AC:

AN:

1150

American (AMR)

AF:

0.0516

AC:

AN:

1144

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

AN:

1030

East Asian (EAS)

AF:

0.0603

AC:

AN:

812

South Asian (SAS)

AF:

0.00636

AC:

AN:

7070

European-Finnish (FIN)

AF:

0.0154

AC:

AN:

1882

Middle Eastern (MID)

AF:

0.0425

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.0217

AC:

1096

AN:

50548

Other (OTH)

AF:

0.0295

AC:

AN:

2476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0426

AC:

6484

AN:

152156

Hom.:

175

Cov.:

AF XY:

0.0423

AC XY:

3150

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0793

AC:

3291

AN:

41488

American (AMR)

AF:

0.0487

AC:

745

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0563

AC:

195

AN:

3464

East Asian (EAS)

AF:

0.0557

AC:

289

AN:

5192

South Asian (SAS)

AF:

0.00747

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0136

AC:

144

AN:

10586

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0241

AC:

1636

AN:

68002

Other (OTH)

AF:

0.0422

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

317

635

952

1270

1587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0301

Hom.:

144

Bravo

AF:

0.0466

Asia WGS

AF:

0.0300

AC:

105

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.69

(source)

DANN

Benign

0.20

PhyloP100

-0.51

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over