17-39301009-C-T

Variant names:

• chr17-39301009-C-T
• NM_032875.3:c.226G>A

Variant summary

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

The NM_032875.3(FBXL20):​c.226G>A​(p.Asp76Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.29

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 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
FBXL20	NM_032875.3	c.226G>A	p.Asp76Asn	missense_variant	Exon 4 of 15	ENST00000264658.11	NP_116264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL20	ENST00000264658.11	c.226G>A	p.Asp76Asn	missense_variant	Exon 4 of 15	1	NM_032875.3	ENSP00000264658.6
FBXL20	ENST00000394294.7	c.226G>A	p.Asp76Asn	missense_variant	Exon 4 of 14	1		ENSP00000377832.3
FBXL20	ENST00000577399.5	c.232G>A	p.Asp78Asn	missense_variant	Exon 4 of 15	5		ENSP00000462878.1
FBXL20	ENST00000583610.5	c.226G>A	p.Asp76Asn	missense_variant	Exon 4 of 16	2		ENSP00000462271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226G>A (p.D76N) alteration is located in exon 4 (coding exon 4) of the FBXL20 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the aspartic acid (D) at amino acid position 76 to be replaced by an asparagine (N). 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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;D;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D;.;D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;.;D;.
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.70
MutPred		0.51		Gain of MoRF binding (P = 0.1653);Gain of MoRF binding (P = 0.1653);Gain of MoRF binding (P = 0.1653);.;
MVP		0.54
MPC		1.1
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-37457262;