5-15927947-C-T

Variant names:

• chr5-15927947-C-T
• rs765845939
• NM_012304.5:c.185C>T

Variant summary

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

The NM_012304.5(FBXL7):​c.185C>T​(p.Pro62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,564,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: FBXL7 NM_012304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10957456).

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.185C>T	p.Pro62Leu	missense	Exon 3 of 4	NP_036436.1	Q9UJT9-1
	FBXL7	NM_001278317.2		c.44C>T	p.Pro15Leu	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.185C>T	p.Pro62Leu	missense	Exon 3 of 4	ENSP00000423630.1	Q9UJT9-1
	FBXL7	ENST00000510662.1	TSL:1	c.44C>T	p.Pro15Leu	missense	Exon 3 of 4	ENSP00000425184.1	Q9UJT9-2
	FBXL7	ENST00000329673.8	TSL:2	c.59C>T	p.Pro20Leu	missense	Exon 1 of 2	ENSP00000329632.8	J3KNM9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152032 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.0000190 AC: 4 AN: 210402 AF XY: 0.0000269

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000163 AC: 23 AN: 1412882 Hom.: 1 Cov.: 31 AF XY: 0.0000201 AC XY: 14 AN XY: 696392

African (AFR) AF: 0.0000613 AC: 2 AN: 32640

American (AMR) AF: 0.0000246 AC: 1 AN: 40696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22224

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.00 AC: 0 AN: 76998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51376

Middle Eastern (MID) AF: 0.00291 AC: 16 AN: 5496

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085942

Other (OTH) AF: 0.0000172 AC: 1 AN: 58216

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152032 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

African (AFR) AF: 0.0000725 AC: 3 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000249 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.042
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Polyphen		0.90	P
Vest4		0.48
MutPred		0.30		Gain of loop (P = 0.0166)
MVP		0.49
MPC		0.98
ClinPred		0.16	T
GERP RS		4.3
PromoterAI		-0.043	Neutral
Varity_R		0.074
gMVP		0.53
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs765845939; hg19: chr5-15928056; COSMIC: COSV107349330;