19-9810999-C-A

Position:

• chr19-9810999-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017703.3(FBXL12):​c.878G>T​(p.Gly293Val) 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: FBXL12 NM_017703.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

Genes affected

FBXL12 (HGNC:13611): (F-box and leucine rich repeat protein 12) Members of the F-box protein family, such as FBXL12, 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36168814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL12	NM_017703.3	c.878G>T	p.Gly293Val	missense_variant	3/3	ENST00000247977.9	NP_060173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL12	ENST00000247977.9	c.878G>T	p.Gly293Val	missense_variant	3/3	1	NM_017703.3	ENSP00000247977	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

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

Jun 29, 2023

The c.878G>T (p.G293V) alteration is located in exon 3 (coding exon 3) of the FBXL12 gene. This alteration results from a G to T substitution at nucleotide position 878, causing the glycine (G) at amino acid position 293 to be replaced by a valine (V). 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	0.26
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.98	N;.;.
REVEL	Benign	0.16
Sift	Benign	0.031	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.51
MutPred		0.52		Loss of disorder (P = 0.0693);.;.;
MVP		0.51
MPC		0.34
ClinPred		0.45	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.53

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: chr19-9921675;