rs746878388

Variant names:

• chr6-98917631-G-A
• rs746878388
• NM_001278716.2:c.601C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001278716.2(FBXL4):​c.601C>T​(p.Pro201Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.601C>T	p.Pro201Ser	missense_variant	Exon 5 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.601C>T	p.Pro201Ser	missense_variant	Exon 5 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.601C>T	p.Pro201Ser	missense_variant	Exon 4 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250772 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135590

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Uncertain:1

Aug 10, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

The NM_012160.4:c.601C>T (NP_036292.2:p.Pro201Ser) [GRCH38: NC_000006.12:g.98917631G>A] 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

Mar 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 201 of the FBXL4 protein (p.Pro201Ser). This variant is present in population databases (rs746878388, gnomAD 0.0009%). 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: 437604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBXL4 protein function. 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	Benign	0.18
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.58	P;P
Vest4		0.66
MutPred		0.52		Gain of MoRF binding (P = 0.0453);Gain of MoRF binding (P = 0.0453);
MVP		0.60
MPC		0.24
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.66

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

Other links and lift over

dbSNP: rs746878388; hg19: chr6-99365507;