3-48379538-T-C

Position:

• chr3-48379538-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXW12 NM_207102.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0800

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 Likely_benign. Variant got -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 id is 2298166.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW12	NM_207102.2	c.754T>C	p.Tyr252His	missense_variant	7/11	ENST00000296438.9	NP_996985.2
FBXW12	NM_001159929.1	c.697T>C	p.Tyr233His	missense_variant	6/10		NP_001153401.1
FBXW12	NM_001159927.1	c.544T>C	p.Tyr182His	missense_variant	6/10		NP_001153399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW12	ENST00000296438.9	c.754T>C	p.Tyr252His	missense_variant	7/11	1	NM_207102.2	ENSP00000296438.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.31
DANN	Benign	0.39
DEOGEN2	Benign	0.00090	T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.047	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.3	N;N;N;N
REVEL	Benign	0.0090
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.14
MutPred		0.41		Loss of sheet (P = 0.0228);.;.;.;
MVP		0.31
MPC		0.36
ClinPred		0.037	T
GERP RS		0.78
Varity_R		0.028
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs377300971; hg19: chr3-48421028;