5-15928045-C-T

Position:

• chr5-15928045-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012304.5(FBXL7):​c.283C>T​(p.Arg95Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00023 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBXL7 NM_012304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

Genes affected

FBXL7 (HGNC:13604): (F-box and leucine rich repeat protein 7) This gene encodes a member of the F-box protein family which is characterized by a 42-48 amino acid motif, the F-box, which binds to the S-phase kinase-associated protein 1 (Skp1) protein. The F-box proteins constitute one of the four subunits of E3 ubiquitin protein ligases called SCFs (SKP1-Cul1-F-box), which play a role in phosphorylation-dependent ubiquitination of proteins. The F-box proteins are divided into 3 subfamilies based on the other domain in the protein: F-box proteins that also have a WD-40 domain (Fbws subfamily), F-box proteins that also have leucine-rich repeats (Fbls subfamily) and F-box proteins that contain other motifs or lack known protein-interaction domains (Fbxs subfamily). The protein encoded by this gene belongs to the Fbls subfamily. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049638927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL7	NM_012304.5	c.283C>T	p.Arg95Cys	missense_variant	3/4	ENST00000504595.2	NP_036436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL7	ENST00000504595.2	c.283C>T	p.Arg95Cys	missense_variant	3/4	1	NM_012304.5	ENSP00000423630.1
FBXL7	ENST00000510662.1	c.142C>T	p.Arg48Cys	missense_variant	3/4	1		ENSP00000425184.1
FBXL7	ENST00000329673.8	c.157C>T	p.Arg53Cys	missense_variant	1/2	2		ENSP00000329632.8

Frequencies

GnomAD3 genomes AF: 0.00 AC: 14 AN: 145036 Hom.: 0 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.000224 AC: 54 AN: 240678 Hom.: 1 AF XY: 0.000244 AC XY: 32 AN XY: 131016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000393

Gnomad ASJ exome AF: 0.00312

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000227 AC: 155 AN: 683886 Hom.: 1 Cov.: 35 AF XY: 0.000222 AC XY: 79 AN XY: 355752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000423

Gnomad4 ASJ exome AF: 0.00726

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000620

Gnomad4 OTH exome AF: 0.000528

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000965 AC: 14 AN: 145036 Hom.: 0 Cov.: 29 AF XY: 0.0000852 AC XY: 6 AN XY: 70420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.00300

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000153

Gnomad4 OTH AF: 0.000494

Alfa AF: 0.000476 Hom.: 1

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000182 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2022

The c.283C>T (p.R95C) alteration is located in exon 3 (coding exon 3) of the FBXL7 gene. This alteration results from a C to T substitution at nucleotide position 283, causing the arginine (R) at amino acid position 95 to be replaced by a cysteine (C). 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	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.11	T;T;.
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.32
MVP		0.39
MPC		0.99
ClinPred		0.071	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.53

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: rs200615738; hg19: chr5-15928154; COSMIC: COSV61653923;