12-1593915-T-G

Position:

• chr12-1593915-T-G

Variant summary

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

The NM_152441.3(FBXL14):​c.152A>C​(p.Lys51Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXL14 NM_152441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

Genes affected

FBXL14 (HGNC:28624): (F-box and leucine rich repeat protein 14) Members of the F-box protein family, such as FBXL14, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

WNT5B (HGNC:16265): (Wnt family member 5B) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It encodes a protein which shows 94% and 80% amino acid identity to the mouse Wnt5b protein and the human WNT5A protein, respectively. Alternative splicing of this gene generates 2 transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL14	NM_152441.3	c.152A>C	p.Lys51Thr	missense_variant	1/2	ENST00000339235.4	NP_689654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL14	ENST00000339235.4	c.152A>C	p.Lys51Thr	missense_variant	1/2	1	NM_152441.3	ENSP00000344855.3
WNT5B	ENST00000537031.5	c.-58+19074T>G		intron_variant		2		ENSP00000439312.1
WNT5B	ENST00000545811.5	c.-57-37383T>G		intron_variant		2		ENSP00000445395.1
WNT5B	ENST00000539198.5	c.-57-37383T>G		intron_variant		4		ENSP00000438414.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 13, 2024

The c.152A>C (p.K51T) alteration is located in exon 1 (coding exon 1) of the FBXL14 gene. This alteration results from a A to C substitution at nucleotide position 152, causing the lysine (K) at amino acid position 51 to be replaced by a threonine (T). 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	Pathogenic	0.89
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.25
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.013	D
Polyphen		0.84	P
Vest4		0.68
MutPred		0.51		Loss of ubiquitination at K51 (P = 0.0326);
MVP		0.28
MPC		2.1
ClinPred		0.87	D
GERP RS		2.9
Varity_R		0.24
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2094496074; hg19: chr12-1703081;