chr3-48375377-C-G

Position:

• chr3-48375377-C-G

Variant summary

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

The ENST00000436231(FBXW12):​c.-96C>G variant causes a 5 prime UTR premature start codon gain 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBXW12 ENST00000436231 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.240

Genes affected

FBXW12 (HGNC:20729): (F-box and WD repeat domain containing 12) Members of the F-box protein family, such as FBXW12, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603034), 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]

FBXW12 (HGNC:):

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=0.086728334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW12	NM_207102.2	c.310C>G	p.Leu104Val	missense_variant	5/11	ENST00000296438.9	NP_996985.2
FBXW12	NM_001159929.1	c.253C>G	p.Leu85Val	missense_variant	4/10		NP_001153401.1
FBXW12	NM_001159927.1	c.310C>G	p.Leu104Val	missense_variant	5/10		NP_001153399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW12	ENST00000296438.9	c.310C>G	p.Leu104Val	missense_variant	5/11	1	NM_207102.2	ENSP00000296438.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

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 25, 2024

The c.310C>G (p.L104V) alteration is located in exon 5 (coding exon 4) of the FBXW12 gene. This alteration results from a C to G substitution at nucleotide position 310, causing the leucine (L) at amino acid position 104 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	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.41	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.024
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.061	T;T;D
Polyphen		0.20	B;.;.
Vest4		0.17
MutPred		0.50		Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);
MVP		0.17
MPC		0.078
ClinPred		0.21	T
GERP RS		-1.9
Varity_R		0.044
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs1575358175; hg19: chr3-48416867;