chr6-98874431-C-T

Position:

chr6-98874431-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001278716.2(FBXL4):c.1713G>A(p.Met571Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000443 in 1,604,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.85

Variant links:

Genes affected

FBXL4 (HGNC:13601): (F-box and leucine rich repeat protein 4) This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

FBXL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27003974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL4	NM_001278716.2 linkuse as main transcript	c.1713G>A	p.Met571Ile	missense_variant	10/10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7 linkuse as main transcript	c.1713G>A	p.Met571Ile	missense_variant	10/10	1	NM_001278716.2	ENSP00000358247	P1
FBXL4	ENST00000229971.2 linkuse as main transcript	c.1713G>A	p.Met571Ile	missense_variant	9/9	1		ENSP00000229971	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000167

AC:

AN:

238822

Hom.:

AF XY:

0.0000232

AC XY:

AN XY:

129428

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000461

AC:

AN:

1452010

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

722410

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.00

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:

0.0000586

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13

Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Aug 10, 2017

The NM_012160.4:c.1713G>A (NP_036292.2:p.Met571Ile) [GRCH38: NC_000006.12:g.98874431C>T] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Conflicting Evidence based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 16, 2022

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 571 of the FBXL4 protein (p.Met571Ile). This variant is present in population databases (rs767419935, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 437797). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.059

T;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.12

Sift

Benign

0.45

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.051

B;B

Vest4

0.54

MutPred

0.36

Gain of catalytic residue at M571 (P = 0.1044);Gain of catalytic residue at M571 (P = 0.1044);

MVP

0.29

MPC

0.079

ClinPred

0.30

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over