3-48372822-C-A

Position:

• chr3-48372822-C-A

Variant summary

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

The NM_207102.2(FBXW12):​c.55C>A​(p.Leu19Met) 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. 13/20 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: FBXW12 NM_207102.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

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=0.15140048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW12	NM_207102.2	c.55C>A	p.Leu19Met	missense_variant	2/11	ENST00000296438.9	NP_996985.2
FBXW12	NM_001159927.1	c.55C>A	p.Leu19Met	missense_variant	2/10		NP_001153399.1
FBXW12	NM_001159929.1	c.34-486C>A		intron_variant			NP_001153401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW12	ENST00000296438.9	c.55C>A	p.Leu19Met	missense_variant	2/11	1	NM_207102.2	ENSP00000296438.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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 02, 2023

The c.55C>A (p.L19M) alteration is located in exon 2 (coding exon 1) of the FBXW12 gene. This alteration results from a C to A substitution at nucleotide position 55, causing the leucine (L) at amino acid position 19 to be replaced by a methionine (M). 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	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0064	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.063
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.74	P;.
Vest4		0.15
MutPred		0.65		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.12
MPC		0.091
ClinPred		0.16	T
GERP RS		-1.9
Varity_R		0.097
gMVP		0.084

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-48414312;