12-116911336-A-G

Variant names:

• chr12-116911336-A-G
• rs1050077671
• NM_153348.3:c.299A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_153348.3(FBXW8):​c.299A>G​(p.Asp100Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,283,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: FBXW8 NM_153348.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• Publications: 1 publications found

Genes affected

FBXW8 (HGNC:13597): (F-box and WD repeat domain containing 8) This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three 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 contains a WD-40 domain, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4199142).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153348.3. 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
	FBXW8	NM_153348.3	MANE Select	c.299A>G	p.Asp100Gly	missense	Exon 1 of 11	NP_699179.2
	FBXW8	NM_012174.2		c.120+179A>G		intron	N/A	NP_036306.1	Q8N3Y1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW8	ENST00000652555.1	MANE Select	c.299A>G	p.Asp100Gly	missense	Exon 1 of 11	ENSP00000498999.1	Q8N3Y1-1
	FBXW8	ENST00000455858.2	TSL:1	c.120+179A>G		intron	N/A	ENSP00000389144.2	Q8N3Y1-2
	FBXW8	ENST00000971034.1		c.299A>G	p.Asp100Gly	missense	Exon 1 of 11	ENSP00000641093.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1314 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: 0.00

GnomAD4 exome AF: 0.000120 AC: 136 AN: 1131060 Hom.: 0 Cov.: 37 AF XY: 0.000125 AC XY: 68 AN XY: 542256

African (AFR) AF: 0.0000429 AC: 1 AN: 23320

American (AMR) AF: 0.000111 AC: 1 AN: 8986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15202

East Asian (EAS) AF: 0.00 AC: 0 AN: 26956

South Asian (SAS) AF: 0.0000311 AC: 1 AN: 32204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3118

European-Non Finnish (NFE) AF: 0.000137 AC: 130 AN: 951472

Other (OTH) AF: 0.0000656 AC: 3 AN: 45760

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67996

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000110

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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.34
Sift	Benign	0.055	T
Sift4G	Benign	0.26	T
Polyphen		0.0090	B
Vest4		0.14
MutPred		0.59		Gain of sheet (P = 0.0049)
MVP		0.85
MPC		0.20
ClinPred		0.95	D
GERP RS		4.1
PromoterAI		-0.0075	Neutral
Varity_R		0.37
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1050077671; hg19: chr12-117349141;