chr7-102813359-C-T

Variant names:

• chr7-102813359-C-T
• rs1250897234
• ENST00000440067.4:c.2461G>A

Variant summary

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

The NM_001394494.2(FBXL13):​c.2461G>A​(p.Glu821Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBXL13 NM_001394494.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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]

FAM185A (HGNC:22412): (family with sequence similarity 185 member A)

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=0.099194705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL13	NM_001394494.2	c.2461G>A	p.Glu821Lys	missense_variant	Exon 21 of 21		NP_001381423.1
FBXL13	NM_145032.3	c.2191G>A	p.Glu731Lys	missense_variant	Exon 20 of 20		NP_659469.3
FBXL13	NM_001287150.2	c.2107G>A	p.Glu703Lys	missense_variant	Exon 19 of 19		NP_001274079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL13	ENST00000440067.4	c.2461G>A	p.Glu821Lys	missense_variant	Exon 21 of 21	3		ENSP00000390126.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249576 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134812

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460292 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726308

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2191G>A (p.E731K) alteration is located in exon 20 (coding exon 18) of the FBXL13 gene. This alteration results from a G to A substitution at nucleotide position 2191, causing the glutamic acid (E) at amino acid position 731 to be replaced by a lysine (K). 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	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0042	.;T;T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.84	T;.;T;D;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.099	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.026
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		0.56	P;B;B;P;P
Vest4		0.24
MutPred		0.35		.;Gain of methylation at E731 (P = 0.0156);Gain of methylation at E731 (P = 0.0156);.;.;
MVP		0.23
MPC		0.15
ClinPred		0.085	T
GERP RS		1.1
Varity_R		0.095
gMVP		0.35

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: rs1250897234; hg19: chr7-102453806;