chr5-15927980-C-T

Variant names:

• chr5-15927980-C-T
• rs748177035
• NM_012304.5:c.218C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012304.5(FBXL7):​c.218C>T​(p.Ser73Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S73W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBXL7 NM_012304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90
• Publications: 3 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27575076).

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.218C>T	p.Ser73Leu	missense	Exon 3 of 4	NP_036436.1	Q9UJT9-1
	FBXL7	NM_001278317.2		c.77C>T	p.Ser26Leu	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.218C>T	p.Ser73Leu	missense	Exon 3 of 4	ENSP00000423630.1	Q9UJT9-1
	FBXL7	ENST00000510662.1	TSL:1	c.77C>T	p.Ser26Leu	missense	Exon 3 of 4	ENSP00000425184.1	Q9UJT9-2
	FBXL7	ENST00000329673.8	TSL:2	c.92C>T	p.Ser31Leu	missense	Exon 1 of 2	ENSP00000329632.8	J3KNM9

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233110 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.95e-7 AC: 1 AN: 1439650 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713040

African (AFR) AF: 0.00 AC: 0 AN: 33256

American (AMR) AF: 0.00 AC: 0 AN: 43570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24366

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.00 AC: 0 AN: 82304

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099134

Other (OTH) AF: 0.00 AC: 0 AN: 59336

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.029	D
Polyphen		0.67	P
Vest4		0.54
MutPred		0.22		Loss of phosphorylation at S73 (P = 0.0061)
MVP		0.40
MPC		0.66
ClinPred		0.70	D
GERP RS		5.5
PromoterAI		-0.041	Neutral
Varity_R		0.20
gMVP		0.38
Mutation Taster		=30/70	disease causing

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: rs748177035; hg19: chr5-15928089; COSMIC: COSV61640610;