rs746074416

Variant names:

• chr3-48375413-A-C
• rs746074416
• NM_207102.2:c.346A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207102.2(FBXW12):​c.346A>C​(p.Lys116Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FBXW12 NM_207102.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18054041).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207102.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW12	NM_207102.2	MANE Select	c.346A>C	p.Lys116Gln	missense	Exon 5 of 11	NP_996985.2	Q6X9E4-1
	FBXW12	NM_001159929.1		c.289A>C	p.Lys97Gln	missense	Exon 4 of 10	NP_001153401.1	Q6X9E4-3
	FBXW12	NM_001159927.1		c.346A>C	p.Lys116Gln	missense	Exon 5 of 10	NP_001153399.1	Q6X9E4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW12	ENST00000296438.9	TSL:1 MANE Select	c.346A>C	p.Lys116Gln	missense	Exon 5 of 11	ENSP00000296438.5	Q6X9E4-1
	FBXW12	ENST00000445170.5	TSL:1	c.289A>C	p.Lys97Gln	missense	Exon 4 of 10	ENSP00000406139.1	Q6X9E4-3
	FBXW12	ENST00000415155.5	TSL:1	c.346A>C	p.Lys116Gln	missense	Exon 5 of 10	ENSP00000414683.1	Q6X9E4-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249812 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460588 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726570

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.0000450 AC: 2 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111660

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.069
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.17
MutPred		0.44		Loss of ubiquitination at K116 (P = 0.0059)
MVP		0.51
MPC		0.42
ClinPred		0.39	T
GERP RS		1.5
Varity_R		0.16
gMVP		0.22
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs746074416; hg19: chr3-48416903;