chr7-102854851-C-T

Variant names:

• chr7-102854851-C-T
• rs907099633
• ENST00000440067.4:c.1915G>A

Variant summary

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

The ENST00000440067.4(FBXL13):​c.1915G>A​(p.Val639Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000451 in 1,552,788 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXL13 ENST00000440067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.31
• 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=0.22960395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL13	NM_001394494.2	c.1915G>A	p.Val639Met	missense_variant	Exon 18 of 21		NP_001381423.1
FBXL13	NM_145032.3	c.1645G>A	p.Val549Met	missense_variant	Exon 17 of 20		NP_659469.3
FBXL13	NM_001111038.2	c.1645G>A	p.Val549Met	missense_variant	Exon 17 of 19		NP_001104508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL13	ENST00000440067.4	c.1915G>A	p.Val639Met	missense_variant	Exon 18 of 21	3		ENSP00000390126.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400686 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 699200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31770

American (AMR) AF: 0.0000244 AC: 1 AN: 41030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.00 AC: 0 AN: 80628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066666

Other (OTH) AF: 0.00 AC: 0 AN: 58110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.000327 AC: 5 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1645G>A (p.V549M) alteration is located in exon 17 (coding exon 15) of the FBXL13 gene. This alteration results from a G to A substitution at nucleotide position 1645, causing the valine (V) at amino acid position 549 to be replaced by a methionine (M). 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	0.093
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0016	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.64	.;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		-1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.82	N;N;.;N
REVEL	Benign	0.0070
Sift	Benign	0.068	T;T;.;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.34	B;B;.;B
Vest4		0.055
MutPred		0.33		Gain of disorder (P = 0.0634);Gain of disorder (P = 0.0634);.;Gain of disorder (P = 0.0634);
MVP		0.040
MPC		0.10
ClinPred		0.098	T
GERP RS		-4.6
Varity_R		0.053
gMVP		0.23
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs907099633; hg19: chr7-102495298;