Genetic Variant NM_024963.6:c.1919G>T (chr7-5491312-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024963.6(FBXL18):c.1919G>T(p.Cys640Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FBXL18
NM_024963.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.80

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL18	NM_024963.6 link	c.1919G>T	p.Cys640Phe	missense_variant	Exon 4 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.1919G>T	p.Cys640Phe	missense_variant	Exon 4 of 5	5	NM_024963.6	ENSP00000371805.3	Q96ME1-4
FBXL18	ENST00000458142.1 link	c.1568G>T	p.Cys523Phe	missense_variant	Exon 2 of 3	2		ENSP00000405896.1	A0A994ENR3
FBXL18	ENST00000415009.5 link	n.1919G>T		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000415064.1	Q96ME1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

242512

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1459620

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111574

Other (OTH)

AF:

0.00

AC:

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1919G>T (p.C640F) alteration is located in exon 4 (coding exon 4) of the FBXL18 gene. This alteration results from a G to T substitution at nucleotide position 1919, causing the cysteine (C) at amino acid position 640 to be replaced by a phenylalanine (F). 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

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.80

MutationAssessor

Benign

2.0

PhyloP100

5.8

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Benign

0.082

Polyphen

0.85

Vest4

0.81

MutPred

0.80

Loss of catalytic residue at L641 (P = 0.0233);

MVP

0.81

MPC

1.4

ClinPred

0.99

GERP RS

4.0

gMVP

0.89

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.1919G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over