12-48925371-C-G

Position:

• chr12-48925371-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016594.3(FKBP11):​c.58G>C​(p.Ala20Pro) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKBP11 NM_016594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.468

Genes affected

FKBP11 (HGNC:18624): (FKBP prolyl isomerase 11) FKBP11 belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. The peptidyl-prolyl isomerase activity of FKBP proteins is inhibited by the immunosuppressant compounds FK506 and rapamycin (Rulten et al., 2006 [PubMed 16596453]).[supplied by OMIM, Mar 2008]

ENSG00000272822 (HGNC:):

CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2622205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP11	NM_016594.3	c.58G>C	p.Ala20Pro	missense_variant	1/6	ENST00000550765.6	NP_057678.1
FKBP11	NM_001143782.2	c.58G>C	p.Ala20Pro	missense_variant	1/6		NP_001137254.1
FKBP11	XM_047428940.1	c.-89G>C		5_prime_UTR_variant	1/6		XP_047284896.1
FKBP11	XM_047428939.1	c.90-249G>C		intron_variant			XP_047284895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP11	ENST00000550765.6	c.58G>C	p.Ala20Pro	missense_variant	1/6	1	NM_016594.3	ENSP00000449751.1
ENSG00000272822	ENST00000398092.4	c.384+14284G>C		intron_variant		3		ENSP00000438507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.58G>C (p.A20P) alteration is located in exon 1 (coding exon 1) of the FKBP11 gene. This alteration results from a G to C substitution at nucleotide position 58, causing the alanine (A) at amino acid position 20 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.072	B;.;.
Vest4		0.30
MutPred		0.69		Gain of disorder (P = 0.0223);Gain of disorder (P = 0.0223);Gain of disorder (P = 0.0223);
MVP		0.77
MPC		0.25
ClinPred		0.13	T
GERP RS		3.5
Varity_R		0.42
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49319154;