Genetic Variant NM_153348.3:c.222C>T (chr12-116911259-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_153348.3(FBXW8):c.222C>T(p.Ala74Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,245,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00092 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

FBXW8
NM_153348.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.77

Publications

0 publications found

Variant links:

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]

FBXW8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 12-116911259-C-T is Benign according to our data. Variant chr12-116911259-C-T is described in ClinVar as Benign. ClinVar VariationId is 721845.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.77 with no splicing effect.

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.222C>T	p.Ala74Ala	synonymous	Exon 1 of 11	NP_699179.2
	FBXW8	NM_012174.2		c.120+102C>T		intron	N/A	NP_036306.1	Q8N3Y1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXW8	ENST00000652555.1	MANE Select	c.222C>T	p.Ala74Ala	synonymous	Exon 1 of 11	ENSP00000498999.1	Q8N3Y1-1
FBXW8	ENST00000455858.2	TSL:1	c.120+102C>T		intron	N/A	ENSP00000389144.2	Q8N3Y1-2
FBXW8	ENST00000971034.1		c.222C>T	p.Ala74Ala	synonymous	Exon 1 of 11	ENSP00000641093.1

Frequencies

GnomAD3 genomes

AF:

0.000891

AC:

135

AN:

151526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

0.000961

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1094264

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

519104

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

22902

American (AMR)

AF:

0.000357

AC:

AN:

8400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14514

East Asian (EAS)

AF:

0.00

AC:

AN:

26642

South Asian (SAS)

AF:

0.0000439

AC:

AN:

22766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2946

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

930026

Other (OTH)

AF:

0.000339

AC:

AN:

44198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000923

AC:

140

AN:

151636

Hom.:

Cov.:

AF XY:

0.000944

AC XY:

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.00324

AC:

134

AN:

41336

American (AMR)

AF:

0.000262

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67826

Other (OTH)

AF:

0.000951

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.00109

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.6

(source)

DANN

Benign

0.90

PhyloP100

-1.8

PromoterAI

-0.062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over