5-15928102-A-G

Variant names:

• chr5-15928102-A-G
• rs746745451
• NM_012304.5:c.340A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012304.5(FBXL7):​c.340A>G​(p.Ile114Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I114L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FBXL7 NM_012304.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.500
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09064528).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL7	NM_012304.5	MANE Select	c.340A>G	p.Ile114Val	missense	Exon 3 of 4	NP_036436.1	Q9UJT9-1
	FBXL7	NM_001278317.2		c.199A>G	p.Ile67Val	missense	Exon 3 of 4	NP_001265246.1	Q9UJT9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL7	ENST00000504595.2	TSL:1 MANE Select	c.340A>G	p.Ile114Val	missense	Exon 3 of 4	ENSP00000423630.1	Q9UJT9-1
	FBXL7	ENST00000510662.1	TSL:1	c.199A>G	p.Ile67Val	missense	Exon 3 of 4	ENSP00000425184.1	Q9UJT9-2
	FBXL7	ENST00000329673.8	TSL:2	c.214A>G	p.Ile72Val	missense	Exon 1 of 2	ENSP00000329632.8	J3KNM9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424850 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 709066

⚠️ 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: 32426

American (AMR) AF: 0.00 AC: 0 AN: 43528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24662

East Asian (EAS) AF: 0.00 AC: 0 AN: 36040

South Asian (SAS) AF: 0.00 AC: 0 AN: 85854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49272

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5562

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089674

Other (OTH) AF: 0.00 AC: 0 AN: 57832

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.6
DANN	Benign	0.77
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N
PhyloP100		0.50
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.035
Sift	Benign	0.50	T
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.24
MutPred		0.59		Gain of helix (P = 0.0854)
MVP		0.56
MPC		0.61
ClinPred		0.12	T
GERP RS		-0.68
PromoterAI		0.016	Neutral
Varity_R		0.031
gMVP		0.44
Mutation Taster		=83/17	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: rs746745451; hg19: chr5-15928211;