12-48923806-G-A

Position:

• chr12-48923806-G-A

Variant summary

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

The NM_016594.3(FKBP11):​c.364C>T​(p.Arg122Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: FKBP11 NM_016594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.895

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=0.11851394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP11	NM_016594.3	c.364C>T	p.Arg122Trp	missense_variant	5/6	ENST00000550765.6	NP_057678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP11	ENST00000550765.6	c.364C>T	p.Arg122Trp	missense_variant	5/6	1	NM_016594.3	ENSP00000449751.1
ENSG00000272822	ENST00000398092.4	c.384+15849C>T		intron_variant		3		ENSP00000438507.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251450 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135904

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.000289 AC XY: 210 AN XY: 727230

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.000310

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74434

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000218

EpiControl AF: 0.000296

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

Oct 06, 2022

The c.364C>T (p.R122W) alteration is located in exon 5 (coding exon 5) of the FKBP11 gene. This alteration results from a C to T substitution at nucleotide position 364, causing the arginine (R) at amino acid position 122 to be replaced by a tryptophan (W). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;D;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.5	.;M;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.29
MVP		0.95
MPC		0.73
ClinPred		0.41	T
GERP RS		0.86
Varity_R		0.62
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs117472187; hg19: chr12-49317589;