7-5481867-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
FBXL18NM_024963.6 linkc.2065G>A p.Asp689Asn missense_variant Exon 5 of 5 ENST00000382368.8 NP_079239.3 Q96ME1-4Q96D16
FBXL18NM_001367780.1 linkc.1765G>A p.Asp589Asn missense_variant Exon 5 of 5 NP_001354709.1
FBXL18NM_001367781.1 linkc.1765G>A p.Asp589Asn missense_variant Exon 5 of 5 NP_001354710.1
FBXL18NM_001363441.2 linkc.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
FBXL18ENST00000382368.8 linkc.2065G>A p.Asp689Asn missense_variant Exon 5 of 5 5 NM_024963.6 ENSP00000371805.3 Q96ME1-4
FBXL18ENST00000415009.5 linkn.2000+9364G>A intron_variant Intron 4 of 6 2 ENSP00000415064.1 Q96ME1-2

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
show subpopulations
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
LINK: link

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; API