Genetic Variant FBXW12:p.Tyr252His (chr3-48379538-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_207102.2(FBXW12):c.754T>C(p.Tyr252His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y252N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FBXW12
NM_207102.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0800

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_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04709834).

BP6

Variant 3-48379538-T-C is Benign according to our data. Variant chr3-48379538-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2298166.Status of the report is criteria_provided_single_submitter, 1 stars.

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.754T>C	p.Tyr252His	missense	Exon 7 of 11	NP_996985.2	Q6X9E4-1
FBXW12	NM_001159929.1		c.697T>C	p.Tyr233His	missense	Exon 6 of 10	NP_001153401.1	Q6X9E4-3
FBXW12	NM_001159927.1		c.544T>C	p.Tyr182His	missense	Exon 6 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.754T>C	p.Tyr252His	missense	Exon 7 of 11	ENSP00000296438.5	Q6X9E4-1
FBXW12	ENST00000445170.5	TSL:1	c.697T>C	p.Tyr233His	missense	Exon 6 of 10	ENSP00000406139.1	Q6X9E4-3
FBXW12	ENST00000415155.5	TSL:1	c.544T>C	p.Tyr182His	missense	Exon 6 of 10	ENSP00000414683.1	Q6X9E4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.14

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.31

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.00090

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.56

M_CAP

Benign

0.0064

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

-0.080

PrimateAI

Benign

0.35

PROVEAN

Benign

1.3

REVEL

Benign

0.0090

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.14

MutPred

0.41

Loss of sheet (P = 0.0228)

MVP

0.31

MPC

0.36

ClinPred

0.037

GERP RS

0.78

Varity_R

0.028

gMVP

0.14

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over