17-39281428-G-C

Position:

• chr17-39281428-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032875.3(FBXL20):​c.657C>G​(p.His219Gln) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXL20 NM_032875.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

Genes affected

FBXL20 (HGNC:24679): (F-box and leucine rich repeat protein 20) Members of the F-box protein family, such as FBXL20, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22741488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL20	NM_032875.3	c.657C>G	p.His219Gln	missense_variant	9/15	ENST00000264658.11	NP_116264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL20	ENST00000264658.11	c.657C>G	p.His219Gln	missense_variant	9/15	1	NM_032875.3	ENSP00000264658.6
FBXL20	ENST00000394294.7	c.561C>G	p.His187Gln	missense_variant	8/14	1		ENSP00000377832.3
FBXL20	ENST00000577399.5	c.663C>G	p.His221Gln	missense_variant	9/15	5		ENSP00000462878.1
FBXL20	ENST00000583610.5	c.657C>G	p.His219Gln	missense_variant	9/16	2		ENSP00000462271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.657C>G (p.H219Q) alteration is located in exon 9 (coding exon 9) of the FBXL20 gene. This alteration results from a C to G substitution at nucleotide position 657, causing the histidine (H) at amino acid position 219 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Uncertain	0.60	D;D;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D;.;D;.
REVEL	Benign	0.18
Sift	Benign	0.18	T;.;T;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.035	B;B;P;.
Vest4		0.43
MutPred		0.52		Gain of solvent accessibility (P = 0.0137);Gain of solvent accessibility (P = 0.0137);.;.;
MVP		0.29
MPC		0.91
ClinPred		0.86	D
GERP RS		2.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.50
gMVP		0.64

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: rs1248756291; hg19: chr17-37437681;