Genetic Variant NM_003602.5:c.216C>A (chr7-73329400-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003602.5(FKBP6):c.216C>A(p.Phe72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FKBP6
NM_003602.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0460

Publications

6 publications found

Variant links:

Genes affected

FKBP6 (HGNC:3722): (FKBP prolyl isomerase family member 6 (inactive)) The protein encoded by this gene is a cis-trans peptidyl-prolyl isomerase that may function in immunoregulation and basic cellular processes involving protein folding and trafficking. This gene is located in a chromosomal region that is deleted in Williams-Beuren syndrome. Defects in this gene may cause male infertility. There are multiple pseudogenes for this gene located nearby on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

FKBP6 Gene-Disease associations (from GenCC):

spermatogenic failure 77
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

FKBP6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP6	NM_003602.5 link	c.216C>A	p.Phe72Leu	missense_variant	Exon 3 of 9	ENST00000252037.5	NP_003593.3	O75344-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP6	ENST00000252037.5 link	c.216C>A	p.Phe72Leu	missense_variant	Exon 3 of 9	1	NM_003602.5	ENSP00000252037.4		O75344-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1457548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725438

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108078

Other (OTH)

AF:

0.00

AC:

AN:

60262

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000155

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;.;D

Eigen

Benign

0.11

Eigen_PC

Benign

-0.064

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.5

.;.;M

PhyloP100

-0.046

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0060

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.81

MutPred

0.93

.;.;Gain of disorder (P = 0.1429);

MVP

0.62

MPC

1.1

ClinPred

1.0

GERP RS

-1.9

Varity_R

0.81

gMVP

0.91

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.54

Position offset: -40

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over