6-98926884-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001278716.2(FBXL4):c.105T>A(p.His35Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,614,076 control chromosomes in the GnomAD database, including 775 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H35R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 59 hom., cov: 32)

Exomes 𝑓: 0.030 ( 716 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.159

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome 13
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

FBXL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.55467 (below the threshold of 3.09). Trascript score misZ: 1.2845 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, mitochondrial DNA depletion syndrome 13.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030468106).

BP6

Variant 6-98926884-A-T is Benign according to our data. Variant chr6-98926884-A-T is described in ClinVar as [Benign]. Clinvar id is 260207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3510/152230) while in subpopulation NFE AF = 0.0355 (2417/67998). AF 95% confidence interval is 0.0344. There are 59 homozygotes in GnomAd4. There are 1608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2 link	c.105T>A	p.His35Gln	missense_variant	Exon 4 of 10	ENST00000369244.7	NP_001265645.1	Q9UKA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7 link	c.105T>A	p.His35Gln	missense_variant	Exon 4 of 10	1	NM_001278716.2	ENSP00000358247.1		Q9UKA2
FBXL4	ENST00000229971.2 link	c.105T>A	p.His35Gln	missense_variant	Exon 3 of 9	1		ENSP00000229971.1		Q9UKA2

Frequencies

GnomAD3 genomes

AF:

0.0231

AC:

3510

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00739

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0265

Gnomad ASJ

AF:

0.0505

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00896

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0356

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0220

AC:

5523

AN:

251384

AF XY:

0.0225

show subpopulations

Gnomad AFR exome

AF:

0.00572

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0453

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0333

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0300

AC:

43863

AN:

1461846

Hom.:

716

Cov.:

AF XY:

0.0296

AC XY:

21509

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00490

AC:

164

AN:

33480

American (AMR)

AF:

0.0185

AC:

827

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0455

AC:

1188

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00508

AC:

438

AN:

86258

European-Finnish (FIN)

AF:

0.0116

AC:

619

AN:

53408

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0348

AC:

38739

AN:

1111976

Other (OTH)

AF:

0.0296

AC:

1788

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2528

5056

7584

10112

12640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0231

AC:

3510

AN:

152230

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1608

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00739

AC:

307

AN:

41544

American (AMR)

AF:

0.0264

AC:

404

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0505

AC:

175

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00373

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00896

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0355

AC:

2417

AN:

67998

Other (OTH)

AF:

0.0227

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

181

362

543

724

905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0324

Hom.:

Bravo

AF:

0.0244

TwinsUK

AF:

0.0353

AC:

131

ALSPAC

AF:

0.0366

AC:

141

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0349

AC:

300

ExAC

AF:

0.0214

AC:

2598

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0395

EpiControl

AF:

0.0385

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 13

Benign:1

Aug 10, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:reference population

The NM_012160.4:c.105T>A (NP_036292.2:p.His35Gln) [GRCH38: NC_000006.12:g.98926884A>T] variant in FBXL4 gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 13. BS2:Observation of the variant is in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 13. 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 Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

.;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.16

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.069

Sift

Benign

0.15

T;T

Sift4G

Uncertain

0.036

D;D

Polyphen

0.090

B;B

Vest4

0.066

MutPred

0.33

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MPC

0.069

ClinPred

0.011

GERP RS

4.4

Varity_R

0.13

gMVP

0.44

Mutation Taster

=99/1

polymorphism (auto)

(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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6-98926884-A-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