Genetic Variant FBXW12:p.Gln67Lys (chr3-48373618-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207102.2(FBXW12):c.199C>A(p.Gln67Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000014 ( 0 hom. )

Consequence

FBXW12
NM_207102.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.604

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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=0.11127174).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXW12	NM_207102.2	MANE Select	c.199C>A	p.Gln67Lys	missense	Exon 4 of 11	NP_996985.2	Q6X9E4-1
FBXW12	NM_001159929.1		c.142C>A	p.Gln48Lys	missense	Exon 3 of 10	NP_001153401.1	Q6X9E4-3
FBXW12	NM_001159927.1		c.199C>A	p.Gln67Lys	missense	Exon 4 of 10	NP_001153399.1	Q6X9E4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXW12	ENST00000296438.9	TSL:1 MANE Select	c.199C>A	p.Gln67Lys	missense	Exon 4 of 11	ENSP00000296438.5	Q6X9E4-1
FBXW12	ENST00000445170.5	TSL:1	c.142C>A	p.Gln48Lys	missense	Exon 3 of 10	ENSP00000406139.1	Q6X9E4-3
FBXW12	ENST00000415155.5	TSL:1	c.199C>A	p.Gln67Lys	missense	Exon 4 of 10	ENSP00000414683.1	Q6X9E4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.2

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.023

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.40

M_CAP

Benign

0.0030

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.53

PhyloP100

-0.60

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.015

Sift

Benign

0.069

Sift4G

Benign

0.20

Polyphen

0.0030

Vest4

0.16

MutPred

0.60

Gain of methylation at Q67 (P = 0.0038)

MVP

0.18

MPC

0.094

ClinPred

0.058

GERP RS

-0.85

Varity_R

0.19

gMVP

0.27

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over