ENST00000440067.4:c.1499A>G

Variant names:

• chr7-102883464-T-C
• rs562653260
• ENST00000440067.4:c.1499A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000440067.4(FBXL13):​c.1499A>G​(p.Asn500Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000997 in 1,604,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N500D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: FBXL13 ENST00000440067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03
• Publications: 0 publications found

Genes affected

FBXL13 (HGNC:21658): (F-box and leucine rich repeat protein 13) Members of the F-box protein family, such as FBXL13, 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.113681644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL13	NM_001394494.2	c.1499A>G	p.Asn500Ser	missense_variant	Exon 15 of 21		NP_001381423.1
FBXL13	NM_145032.3	c.1229A>G	p.Asn410Ser	missense_variant	Exon 14 of 20		NP_659469.3
FBXL13	NM_001287150.2	c.1229A>G	p.Asn410Ser	missense_variant	Exon 14 of 19		NP_001274079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL13	ENST00000440067.4	c.1499A>G	p.Asn500Ser	missense_variant	Exon 15 of 21	3		ENSP00000390126.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152068 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000495 AC: 12 AN: 242434 AF XY: 0.0000382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000964 AC: 14 AN: 1452812 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 722102

African (AFR) AF: 0.00 AC: 0 AN: 32920

American (AMR) AF: 0.0000234 AC: 1 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 84404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108346

Other (OTH) AF: 0.00 AC: 0 AN: 60024

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74402

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1229A>G (p.N410S) alteration is located in exon 14 (coding exon 12) of the FBXL13 gene. This alteration results from a A to G substitution at nucleotide position 1229, causing the asparagine (N) at amino acid position 410 to be replaced by a serine (S). 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	-0.44	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	.;T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.94	T
PhyloP100		3.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D;D;D;.;D
REVEL	Benign	0.22
Sift	Benign	0.035	D;D;D;.;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.96	D;D;D;.;D
Vest4		0.34
MutPred		0.54		Gain of phosphorylation at N410 (P = 0.0337);Gain of phosphorylation at N410 (P = 0.0337);Gain of phosphorylation at N410 (P = 0.0337);.;Gain of phosphorylation at N410 (P = 0.0337);
MVP		0.29
MPC		0.43
ClinPred		0.46	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.42
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs562653260; hg19: chr7-102523911;