12-116949660-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153348.3(FBXW8):c.631A>G(p.Thr211Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00582 in 1,614,144 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.015 ( 48 hom., cov: 33)

Exomes 𝑓: 0.0049 ( 57 hom. )

Consequence

FBXW8
NM_153348.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.04

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:

ENSG00000274554 (HGNC:):

ENSG00000274554 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027846098).

BP6

Variant 12-116949660-A-G is Benign according to our data. Variant chr12-116949660-A-G is described in ClinVar as [Benign]. Clinvar id is 790127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2259/152256) while in subpopulation AFR AF = 0.0454 (1885/41540). AF 95% confidence interval is 0.0437. There are 48 homozygotes in GnomAd4. There are 1031 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXW8	NM_153348.3 link	c.631A>G	p.Thr211Ala	missense_variant	Exon 4 of 11	ENST00000652555.1	NP_699179.2	Q8N3Y1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXW8	ENST00000652555.1 link	c.631A>G	p.Thr211Ala	missense_variant	Exon 4 of 11		NM_153348.3	ENSP00000498999.1	Q8N3Y1-1
FBXW8	ENST00000455858.2 link	c.433A>G	p.Thr145Ala	missense_variant	Exon 4 of 11	1		ENSP00000389144.2	Q8N3Y1-2
FBXW8	ENST00000309909.10 link	c.319A>G	p.Thr107Ala	missense_variant	Exon 4 of 11	1		ENSP00000310686.6	A0A499FIY5
ENSG00000274554	ENST00000617795.1 link	n.1763T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2254

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00344

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00583

AC:

1466

AN:

251478

AF XY:

0.00495

show subpopulations

Gnomad AFR exome

AF:

0.0476

Gnomad AMR exome

AF:

0.00471

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00399

Gnomad OTH exome

AF:

0.00521

GnomAD4 exome

AF:

0.00488

AC:

7136

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

3290

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0499

AC:

1669

AN:

33478

Gnomad4 AMR exome

AF:

0.00492

AC:

220

AN:

44724

Gnomad4 ASJ exome

AF:

0.00249

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.000128

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.000861

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.00418

AC:

4649

AN:

1112010

Gnomad4 Remaining exome

AF:

0.00717

AC:

433

AN:

60396

Heterozygous variant carriers

383

766

1150

1533

1916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.0148

AC:

2259

AN:

152256

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1031

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0454

AC:

0.0453779

AN:

0.0453779

Gnomad4 AMR

AF:

0.00602

AC:

0.00601543

AN:

0.00601543

Gnomad4 ASJ

AF:

0.00288

AC:

0.00288351

AN:

0.00288351

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000754

AC:

0.000753864

AN:

0.000753864

Gnomad4 NFE

AF:

0.00344

AC:

0.00344006

AN:

0.00344006

Gnomad4 OTH

AF:

0.0109

AC:

0.0108798

AN:

0.0108798

Heterozygous variant carriers

115

230

346

461

576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00816

Hom.:

Bravo

AF:

0.0175

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.0486

AC:

214

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00647

AC:

786

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.19

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.061

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.79

N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.10

Sift

Benign

1.0

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0

B;B

Vest4

0.10

MVP

0.31

MPC

0.13

ClinPred

0.0029

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.028

Mutation Taster

=99/1

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over