12-116949660-A-G

Position:

chr12-116949660-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW8	NM_153348.3 linkuse as main transcript	c.631A>G	p.Thr211Ala	missense_variant	4/11	ENST00000652555.1	NP_699179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW8	ENST00000652555.1 linkuse as main transcript	c.631A>G	p.Thr211Ala	missense_variant	4/11		NM_153348.3	ENSP00000498999	P1	Q8N3Y1-1
FBXW8	ENST00000455858.2 linkuse as main transcript	c.433A>G	p.Thr145Ala	missense_variant	4/11	1		ENSP00000389144		Q8N3Y1-2
FBXW8	ENST00000309909.10 linkuse as main transcript	c.319A>G	p.Thr107Ala	missense_variant	4/11	1		ENSP00000310686
	ENST00000617795.1 linkuse as main transcript	n.1763T>C		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes

AF:

0.00583

AC:

1466

AN:

251478

Hom.:

AF XY:

0.00495

AC XY:

673

AN XY:

135910

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 SAS exome

AF:

0.0000653

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

Gnomad4 AMR exome

AF:

0.00492

Gnomad4 ASJ exome

AF:

0.00249

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.00418

Gnomad4 OTH exome

AF:

0.00717

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

Gnomad4 AMR

AF:

0.00602

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00344

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00634

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 04, 2018	- -

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;.

MutationTaster

Benign

1.0

N;N;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

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