6-98874423-G-C

Variant names:

• chr6-98874423-G-C
• NM_001278716.2:c.1721C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001278716.2(FBXL4):​c.1721C>G​(p.Pro574Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P574P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.78

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38632894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.1721C>G	p.Pro574Arg	missense_variant	Exon 10 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.1721C>G	p.Pro574Arg	missense_variant	Exon 10 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.1721C>G	p.Pro574Arg	missense_variant	Exon 9 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455278 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.11
Sift	Benign	0.11	T;T
Sift4G	Benign	0.096	T;T
Polyphen		0.68	P;P
Vest4		0.58
MutPred		0.53		Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);
MVP		0.45
MPC		0.38
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-99322299;