3-48378488-A-C

Variant names:

• chr3-48378488-A-C
• rs1379022064
• NM_207102.2:c.577A>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.577A>C​(p.Met193Leu) 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: 30)
• Consequence: FBXW12 NM_207102.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28

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

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=0.044030815).
• BP6: Variant 3-48378488-A-C is Benign according to our data. Variant chr3-48378488-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3278220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXW12	NM_207102.2	c.577A>C	p.Met193Leu	missense_variant	Exon 6 of 11	ENST00000296438.9	NP_996985.2
FBXW12	NM_001159929.1	c.520A>C	p.Met174Leu	missense_variant	Exon 5 of 10		NP_001153401.1
FBXW12	NM_001159927.1	c.406-912A>C		intron_variant	Intron 5 of 9		NP_001153399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXW12	ENST00000296438.9	c.577A>C	p.Met193Leu	missense_variant	Exon 6 of 11	1	NM_207102.2	ENSP00000296438.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 20, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0050
DANN	Benign	0.42
DEOGEN2	Benign	0.0058	T;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.40	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	N;N;N
REVEL	Benign	0.023
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.14
MutPred		0.66		Loss of helix (P = 0.2662);.;.;
MVP		0.14
MPC		0.070
ClinPred		0.043	T
GERP RS		-9.0
Varity_R		0.051
gMVP		0.13

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: rs1379022064; hg19: chr3-48419978;