12-116945481-T-C

Position:

• chr12-116945481-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153348.3(FBXW8):​c.541T>C​(p.Phe181Leu) 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 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXW8 NM_153348.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

Genes affected

FBXW8 (HGNC:13597): (F-box and WD repeat domain containing 8) This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene contains a WD-40 domain, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06479898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW8	NM_153348.3	c.541T>C	p.Phe181Leu	missense_variant	3/11	ENST00000652555.1	NP_699179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW8	ENST00000652555.1	c.541T>C	p.Phe181Leu	missense_variant	3/11		NM_153348.3	ENSP00000498999.1
FBXW8	ENST00000455858.2	c.343T>C	p.Phe115Leu	missense_variant	3/11	1		ENSP00000389144.2
FBXW8	ENST00000309909.10	c.229T>C	p.Phe77Leu	missense_variant	3/11	1		ENSP00000310686.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461820 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.541T>C (p.F181L) alteration is located in exon 3 (coding exon 3) of the FBXW8 gene. This alteration results from a T to C substitution at nucleotide position 541, causing the phenylalanine (F) at amino acid position 181 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.031
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.12
MutPred		0.43		Gain of catalytic residue at W177 (P = 0);.;
MVP		0.39
MPC		0.15
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.047

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: rs144672119; hg19: chr12-117383286;