Genetic Variant FBXW12:p.Gln157His (chr3-48378382-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The ENST00000436231.5(FBXW12):c.1-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FBXW12
ENST00000436231.5 splice_acceptor, intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.528

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: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15584415 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000436231.5. 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.471G>C	p.Gln157His	missense	Exon 6 of 11	NP_996985.2	Q6X9E4-1
FBXW12	NM_001159929.1		c.414G>C	p.Gln138His	missense	Exon 5 of 10	NP_001153401.1	Q6X9E4-3
FBXW12	NM_001159927.1		c.406-1018G>C		intron	N/A	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.471G>C	p.Gln157His	missense	Exon 6 of 11	ENSP00000296438.5	Q6X9E4-1
FBXW12	ENST00000445170.5	TSL:1	c.414G>C	p.Gln138His	missense	Exon 5 of 10	ENSP00000406139.1	Q6X9E4-3
FBXW12	ENST00000415155.5	TSL:1	c.406-1018G>C		intron	N/A	ENSP00000414683.1	Q6X9E4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727238

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:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0056

Eigen

Benign

-0.083

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.48

M_CAP

Benign

0.017

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.53

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

REVEL

Benign

0.10

Sift

Benign

0.050

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.18

MutPred

0.47

Loss of helix (P = 0.0376)

MVP

0.34

MPC

0.071

ClinPred

0.20

GERP RS

3.7

Varity_R

0.12

gMVP

0.30

Mutation Taster

=32/68

disease causing

(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