6-152971173-C-T

Variant names:

• chr6-152971173-C-T
• rs144773049
• NM_012177.5:c.1334G>A

Variant summary

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

The NM_012177.5(FBXO5):​c.1334G>A​(p.Arg445Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,453,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: FBXO5 NM_012177.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.30
• Publications: 1 publications found

Genes affected

FBXO5 (HGNC:13584): (F-box protein 5) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. This protein is similar to xenopus early mitotic inhibitor-1 (Emi1), which is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Dec 2008]

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=0.20031947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012177.5. 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
	FBXO5	NM_012177.5	MANE Select	c.1334G>A	p.Arg445Gln	missense	Exon 5 of 5	NP_036309.1	Q9UKT4-1
	FBXO5	NM_001142522.3		c.1196G>A	p.Arg399Gln	missense	Exon 5 of 5	NP_001135994.1	Q9UKT4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO5	ENST00000229758.8	TSL:1 MANE Select	c.1334G>A	p.Arg445Gln	missense	Exon 5 of 5	ENSP00000229758.3	Q9UKT4-1
	FBXO5	ENST00000367241.3	TSL:1	c.1196G>A	p.Arg399Gln	missense	Exon 5 of 5	ENSP00000356210.3	Q9UKT4-2
	FBXO5	ENST00000477822.2	TSL:2	n.1956G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000411 AC: 10 AN: 243472 AF XY: 0.0000532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000617

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1453724 Hom.: 0 Cov.: 31 AF XY: 0.0000291 AC XY: 21 AN XY: 722862

African (AFR) AF: 0.0000303 AC: 1 AN: 32992

American (AMR) AF: 0.0000471 AC: 2 AN: 42494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1109586

Other (OTH) AF: 0.0000166 AC: 1 AN: 60080

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000626 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000547

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.023
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.96	L
PhyloP100		1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.78	P
Vest4		0.15
MVP		0.42
MPC		0.38
ClinPred		0.094	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.53
Mutation Taster		=85/15	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: rs144773049; hg19: chr6-153292308; COSMIC: COSV105066547;