12-1594015-C-T

Variant names:

• chr12-1594015-C-T
• rs1592492599
• NM_152441.3:c.52G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152441.3(FBXL14):​c.52G>A​(p.Gly18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBXL14 NM_152441.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09084684).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152441.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL14	NM_152441.3	MANE Select	c.52G>A	p.Gly18Ser	missense	Exon 1 of 2	NP_689654.1	Q8N1E6
	FBXL14	NM_001405291.1		c.52G>A	p.Gly18Ser	missense	Exon 1 of 2	NP_001392220.1
	FBXL14	NM_001405292.1		c.52G>A	p.Gly18Ser	missense	Exon 1 of 2	NP_001392221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL14	ENST00000339235.4	TSL:1 MANE Select	c.52G>A	p.Gly18Ser	missense	Exon 1 of 2	ENSP00000344855.3	Q8N1E6
	FBXL14	ENST00000923181.1		c.52G>A	p.Gly18Ser	missense	Exon 1 of 2	ENSP00000593240.1
	WNT5B	ENST00000537031.5	TSL:2	c.-58+19174C>T		intron	N/A	ENSP00000439312.1	Q9H1J7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1422852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706104

African (AFR) AF: 0.00 AC: 0 AN: 32958

American (AMR) AF: 0.00 AC: 0 AN: 41344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24624

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 82770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100676

Other (OTH) AF: 0.00 AC: 0 AN: 59080

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	1.8	N
REVEL	Benign	0.085
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.59		Gain of catalytic residue at G18 (P = 0.1044)
MVP		0.27
MPC		1.2
ClinPred		0.45	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.43
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1592492599; hg19: chr12-1703181;