chr7-5500585-A-G

Position:

• chr7-5500585-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024963.6(FBXL18):​c.1684T>C​(p.Ser562Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

Genes affected

FBXL18 (HGNC:21874): (F-box and leucine rich repeat protein 18) The protein encoded by this gene is a member of a family of proteins that contain an approximately 40-amino acid F-box motif. This motif is important for interaction with SKP1 and for targeting some proteins for degradation. The encoded protein has been shown to control the cellular level of FBXL7, a protein that induces mitotic arrest, by targeting it for polyubiquitylation and proteasomal degradation. Members of the F-box protein family, such as FBXL18, are characterized by an approximately 40-amino acid F-box motif. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38075453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL18	NM_024963.6	c.1684T>C	p.Ser562Pro	missense_variant	3/5	ENST00000382368.8	NP_079239.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL18	ENST00000382368.8	c.1684T>C	p.Ser562Pro	missense_variant	3/5	5	NM_024963.6	ENSP00000371805.3
FBXL18	ENST00000458142.1	c.1333T>C	p.Ser445Pro	missense_variant	1/3	2		ENSP00000405896.1
FBXL18	ENST00000415009.5	n.1684T>C		non_coding_transcript_exon_variant	3/7	2		ENSP00000415064.1

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

Mar 01, 2023

The c.1684T>C (p.S562P) alteration is located in exon 3 (coding exon 3) of the FBXL18 gene. This alteration results from a T to C substitution at nucleotide position 1684, causing the serine (S) at amino acid position 562 to be replaced by a proline (P). 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
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.87	P
Vest4		0.45
MutPred		0.40		Loss of helix (P = 0.0068);
MVP		0.81
MPC		0.68
ClinPred		0.81	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.88

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: chr7-5540216;