Genetic Variant ENST00000440067.4:c.1673G>A (chr7-102878436-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000440067.4(FBXL13):c.1673G>A(p.Gly558Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G558A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FBXL13
ENST00000440067.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.94

Publications

0 publications found

Variant links:

Genes affected

FBXL13 (HGNC:21658): (F-box and leucine rich repeat protein 13) Members of the F-box protein family, such as FBXL13, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

FBXL13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
FBXL13	NM_001394494.2 link	c.1673G>A	p.Gly558Glu	missense_variant	Exon 16 of 21	NP_001381423.1
FBXL13	NM_145032.3 link	c.1403G>A	p.Gly468Glu	missense_variant	Exon 15 of 20	NP_659469.3	Q8NEE6-1Q8N1P0
FBXL13	NM_001287150.2 link	c.1403G>A	p.Gly468Glu	missense_variant	Exon 15 of 19	NP_001274079.1	Q8NEE6-2Q8N1P0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL13	ENST00000440067.4 link	c.1673G>A	p.Gly558Glu	missense_variant	Exon 16 of 21	3		ENSP00000390126.2		C9JI88

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446626

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719302

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32820

American (AMR)

AF:

0.00

AC:

AN:

42400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

39100

South Asian (SAS)

AF:

0.00

AC:

AN:

82848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105250

Other (OTH)

AF:

0.00

AC:

AN:

59744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

.;T;T;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;.;D;D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Benign

-0.82

PhyloP100

4.9

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.8

D;D;D;.;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D;D;.;D

Sift4G

Uncertain

0.012

D;D;D;D;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.85

MutPred

0.55

Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);.;Gain of solvent accessibility (P = 0.0766);

MVP

0.32

MPC

0.55

ClinPred

1.0

GERP RS

5.4

Varity_R

0.87

gMVP

0.87

Mutation Taster

=61/39

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over