7-5481867-C-T

Variant names:

• chr7-5481867-C-T
• NM_024963.6:c.2065G>A

Variant summary

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

The NM_024963.6(FBXL18):​c.2065G>A​(p.Asp689Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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: 0.0000034 (0 hom.)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11522806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL18	NM_024963.6	c.2065G>A	p.Asp689Asn	missense_variant	Exon 5 of 5	ENST00000382368.8	NP_079239.3
FBXL18	NM_001367780.1	c.1765G>A	p.Asp589Asn	missense_variant	Exon 5 of 5		NP_001354709.1
FBXL18	NM_001367781.1	c.1765G>A	p.Asp589Asn	missense_variant	Exon 5 of 5		NP_001354710.1
FBXL18	NM_001363441.2	c.2000+9364G>A		intron_variant	Intron 4 of 4		NP_001350370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL18	ENST00000382368.8	c.2065G>A	p.Asp689Asn	missense_variant	Exon 5 of 5	5	NM_024963.6	ENSP00000371805.3
FBXL18	ENST00000415009.5	n.2000+9364G>A		intron_variant	Intron 4 of 6	2		ENSP00000415064.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461452 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2065G>A (p.D689N) alteration is located in exon 5 (coding exon 5) of the FBXL18 gene. This alteration results from a G to A substitution at nucleotide position 2065, causing the aspartic acid (D) at amino acid position 689 to be replaced by an asparagine (N). 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	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.089
Sift	Benign	0.15	T
Sift4G	Benign	0.26	T
Polyphen		0.0030	B
Vest4		0.076
MutPred		0.20		Gain of sheet (P = 0.0477);
MVP		0.46
MPC		0.52
ClinPred		0.47	T
GERP RS		2.9
gMVP		0.39

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: chr7-5521498;