chr3-48378318-G-C

Position:

• chr3-48378318-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_207102.2(FBXW12):​c.407G>C​(p.Gly136Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FBXW12 NM_207102.2 missense, splice_region
• Scores: Splicing: ADA: 0.9647
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW12	NM_207102.2	c.407G>C	p.Gly136Ala	missense_variant, splice_region_variant	6/11	ENST00000296438.9	NP_996985.2
FBXW12	NM_001159929.1	c.350G>C	p.Gly117Ala	missense_variant, splice_region_variant	5/10		NP_001153401.1
FBXW12	NM_001159927.1	c.406-1082G>C		intron_variant			NP_001153399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW12	ENST00000296438.9	c.407G>C	p.Gly136Ala	missense_variant, splice_region_variant	6/11	1	NM_207102.2	ENSP00000296438.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

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

May 21, 2024

The c.407G>C (p.G136A) alteration is located in exon 6 (coding exon 5) of the FBXW12 gene. This alteration results from a G to C substitution at nucleotide position 407, causing the glycine (G) at amino acid position 136 to be replaced by an alanine (A). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.47
MutPred		0.75		Gain of helix (P = 0.0117);.;
MVP		0.70
MPC		0.40
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.37
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.79
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: chr3-48419808;