chr7-102878422-G-T

Variant names:

• chr7-102878422-G-T
• rs199732318
• ENST00000440067.4:c.1687C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000440067.4(FBXL13):​c.1687C>A​(p.Leu563Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000859 in 1,607,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. L563P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: FBXL13 ENST00000440067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.368
• Publications: 4 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0562703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL13	NM_001394494.2	c.1687C>A	p.Leu563Ile	missense_variant	Exon 16 of 21		NP_001381423.1
FBXL13	NM_145032.3	c.1417C>A	p.Leu473Ile	missense_variant	Exon 15 of 20		NP_659469.3
FBXL13	NM_001287150.2	c.1417C>A	p.Leu473Ile	missense_variant	Exon 15 of 19		NP_001274079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL13	ENST00000440067.4	c.1687C>A	p.Leu563Ile	missense_variant	Exon 16 of 21	3		ENSP00000390126.2

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 42 AN: 245734 AF XY: 0.000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.000702

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000884

Gnomad NFE exome AF: 0.0000626

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.0000873 AC: 127 AN: 1455088 Hom.: 0 Cov.: 29 AF XY: 0.0000871 AC XY: 63 AN XY: 723606

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.000183 AC: 8 AN: 43756

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 26010

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39368

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84738

European-Finnish (FIN) AF: 0.000941 AC: 50 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1108936

Other (OTH) AF: 0.000233 AC: 14 AN: 60138

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41498

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10568

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1417C>A (p.L473I) alteration is located in exon 15 (coding exon 13) of the FBXL13 gene. This alteration results from a C to A substitution at nucleotide position 1417, causing the leucine (L) at amino acid position 473 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0014	.;T;T;.;.
Eigen	Benign	-0.029
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T;.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.056	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.37
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.17	N;N;N;.;N
REVEL	Benign	0.033
Sift	Benign	0.090	T;T;T;.;T
Sift4G	Benign	0.072	T;D;D;T;T
Polyphen		0.96	P;B;B;.;B
Vest4		0.48
MVP		0.35
MPC		0.14
ClinPred		0.038	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.18
Mutation Taster		=94/6	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: rs199732318; hg19: chr7-102518869; COSMIC: COSV57546218;