chr3-48373610-C-A

Position:

• chr3-48373610-C-A

Variant summary

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

The NM_207102.2(FBXW12):​c.191C>A​(p.Thr64Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBXW12 NM_207102.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.140

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 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
FBXW12	NM_207102.2	c.191C>A	p.Thr64Lys	missense_variant	4/11	ENST00000296438.9	NP_996985.2
FBXW12	NM_001159929.1	c.134C>A	p.Thr45Lys	missense_variant	3/10		NP_001153401.1
FBXW12	NM_001159927.1	c.191C>A	p.Thr64Lys	missense_variant	4/10		NP_001153399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW12	ENST00000296438.9	c.191C>A	p.Thr64Lys	missense_variant	4/11	1	NM_207102.2	ENSP00000296438.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

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

Apr 09, 2024

The c.191C>A (p.T64K) alteration is located in exon 4 (coding exon 3) of the FBXW12 gene. This alteration results from a C to A substitution at nucleotide position 191, causing the threonine (T) at amino acid position 64 to be replaced by a lysine (K). 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	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Benign	0.084
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.032	D;D;T
Polyphen		0.98	D;.;.
Vest4		0.31
MutPred		0.51		Gain of methylation at T64 (P = 0.0237);.;Gain of methylation at T64 (P = 0.0237);
MVP		0.38
MPC		0.45
ClinPred		0.70	D
GERP RS		2.8
Varity_R		0.52
gMVP		0.49

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: rs971493770; hg19: chr3-48415100;