NM_024963.6:c.1289C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024963.6(FBXL18):c.1289C>T(p.Pro430Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,549,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FBXL18
NM_024963.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

Publications

0 publications found

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]

FBXL18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16010457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL18	NM_024963.6 link	c.1289C>T	p.Pro430Leu	missense_variant	Exon 3 of 5	ENST00000382368.8	NP_079239.3	Q96ME1-4Q96D16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXL18	ENST00000382368.8 link	c.1289C>T	p.Pro430Leu	missense_variant	Exon 3 of 5	5	NM_024963.6	ENSP00000371805.3	Q96ME1-4
FBXL18	ENST00000458142.1 link	c.938C>T	p.Pro313Leu	missense_variant	Exon 1 of 3	2		ENSP00000405896.1	A0A994ENR3
FBXL18	ENST00000415009.5 link	n.1289C>T		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000415064.1	Q96ME1-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000115

AC:

AN:

173402

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1396802

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

690622

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31464

American (AMR)

AF:

0.00

AC:

AN:

33046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22436

East Asian (EAS)

AF:

0.00

AC:

AN:

38952

South Asian (SAS)

AF:

0.00

AC:

AN:

76798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.0000175

AC:

AN:

1086192

Other (OTH)

AF:

0.0000347

AC:

AN:

57682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000870

Hom.:

ExAC

AF:

0.00000853

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1289C>T (p.P430L) alteration is located in exon 3 (coding exon 3) of the FBXL18 gene. This alteration results from a C to T substitution at nucleotide position 1289, causing the proline (P) at amino acid position 430 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

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

M_CAP

Benign

0.044

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

2.8

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.4

REVEL

Benign

0.077

Sift

Benign

0.34

Sift4G

Benign

0.088

Polyphen

0.34

Vest4

0.18

MutPred

0.20

Gain of helix (P = 0.0034);

MVP

0.69

MPC

0.57

ClinPred

0.26

GERP RS

4.5

gMVP

0.22

Mutation Taster

=91/9

polymorphism

(source)

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

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NM_024963.6:c.1289C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over