5-108348416-T-C

Position:

• chr5-108348416-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000542267.7(FBXL17):​c.1489A>G​(p.Met497Val) 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. 13/21 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)
• Consequence: FBXL17 ENST00000542267.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

FBXL17 (HGNC:13615): (F-box and leucine rich repeat protein 17) Members of the F-box protein family, such as FBXL17, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23674372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL17	NM_001163315.3	c.1489A>G	p.Met497Val	missense_variant	4/9	ENST00000542267.7	NP_001156787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL17	ENST00000542267.7	c.1489A>G	p.Met497Val	missense_variant	4/9	1	NM_001163315.3	ENSP00000437464	P1
FBXL17	ENST00000496714.2	c.499A>G	p.Met167Val	missense_variant	3/7	1		ENSP00000418111
FBXL17	ENST00000481160.1	n.145A>G		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Feb 13, 2024

The c.1489A>G (p.M497V) alteration is located in exon 4 (coding exon 4) of the FBXL17 gene. This alteration results from a A to G substitution at nucleotide position 1489, causing the methionine (M) at amino acid position 497 to be replaced by a valine (V). 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	Pathogenic	0.67
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.020	.;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	.;L;.;.
MutationTaster	Benign	0.62	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Benign	0.10
Sift	Benign	0.058	T;D;.;D
Sift4G	Uncertain	0.049	D;D;D;D
Polyphen		0.30, 0.038	.;B;.;B
Vest4		0.59
MutPred		0.36		.;Loss of ubiquitination at K501 (P = 0.0637);.;.;
MVP		0.12
MPC		0.72
ClinPred		0.64	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-107684117;