NM_001278716.2:c.1790A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001278716.2(FBXL4):c.1790A>C(p.Gln597Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,613,216 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.67

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

PP5

Variant 6-98874354-T-G is Pathogenic according to our data. Variant chr6-98874354-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437486.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}. Variant chr6-98874354-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2 link	c.1790A>C	p.Gln597Pro	missense_variant	Exon 10 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.1790A>C	p.Gln597Pro	missense_variant	Exon 10 of 10	1	NM_001278716.2	ENSP00000358247.1		Q9UKA2
FBXL4	ENST00000229971.2 link	c.1790A>C	p.Gln597Pro	missense_variant	Exon 9 of 9	1		ENSP00000229971.1		Q9UKA2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250346

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135306

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:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461046

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000405

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000445

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13

Pathogenic:3

Mar 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_012160.4:c.1790A>C (NP_036292.2:p.Gln597Pro) [GRCH38: NC_000006.12:g.98874354T>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 . 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. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patientâ€™s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant in an 8-year-old female with regression, basal ganglia abnormalities, absent speech, autistic features, hypotonia, spasticity, exercise intolerance, ataxia, severe renal tubular acidosis, scoliosis, primary mitochondrial respiratory chain disease -

not provided

Pathogenic:1Uncertain:1

May 23, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q597P variant has been published in patients who also harbored another variant in the FBXL4 gene with symptoms that include early-onset lactic acidemia, hypotonia, encephalopathy, hyperammonemia, defects in the respiratory chain and mitochondrial DNA depletion (Gai et al. 2013; Morton et al. 2016). The Q597P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q597P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In summary, we interpret this variant as likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Mar 08, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Mar 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBXL4 c.1790A>C (p.Gln597Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250346 control chromosomes (gnomAD). c.1790A>C has been reported in the literature in individuals affected with Leigh Syndrome and Mitochondrial disorder (examples: Gai_2013, Morton_2016, Ballout_2019, Alves_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32445240, 30804983, 23993194, 34052969, 27858371). ClinVar contains an entry for this variant (Variation ID: 437486). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.24

Sift

Benign

0.14

T;T

Sift4G

Uncertain

0.027

D;D

Polyphen

0.99

D;D

Vest4

0.92

MutPred

0.58

Loss of catalytic residue at Q597 (P = 0.0297);Loss of catalytic residue at Q597 (P = 0.0297);

MVP

0.52

MPC

0.12

ClinPred

0.77

GERP RS

6.0

Varity_R

0.51

gMVP

0.87

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

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