chr6-98917587-T-A

Position:

• chr6-98917587-T-A

Variant summary

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

The NM_001278716.2(FBXL4):​c.645A>T​(p.Glu215Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict 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. E215E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.786

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 (HGNC:):

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/exons	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.645A>T	p.Glu215Asp	missense_variant	5/10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.645A>T	p.Glu215Asp	missense_variant	5/10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.645A>T	p.Glu215Asp	missense_variant	4/9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	18
DANN	Benign	0.29
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.7	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.38		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.19
MPC		0.059
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.098
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -17

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: chr6-99365463;