8-144356181-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_012162.4(FBXL6):c.1259C>T(p.Thr420Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,551,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000080 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

FBXL6
NM_012162.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.692

Publications

0 publications found

Variant links:

Genes affected

FBXL6 (HGNC:13603): (F-box and leucine rich repeat protein 6) This gene encodes a member of a family of proteins that are characterized by an F-box motif. The encoded protein also contains leucine-rich repeats. F-box-containing proteins comprise one of the subunits of the SCF (SKP1-cullin-F-box) complex, which functions in phosphorylation-dependent ubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

FBXL6 links:

SLC52A2 (HGNC:30224): (solute carrier family 52 member 2) This gene encodes a membrane protein which belongs to the riboflavin transporter family. In humans, riboflavin must be obtained by intestinal absorption because it cannot be synthesized by the body. The water-soluble vitamin riboflavin is processed to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which then act as intermediaries in many cellular metabolic reactions. Paralogous members of the riboflavin transporter gene family are located on chromosomes 17 and 20. Unlike other members of this family, this gene has higher expression in brain tissue than small intestine. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. Mutations in this gene have been associated with Brown-Vialetto-Van Laere syndrome 2 - an autosomal recessive progressive neurologic disorder characterized by deafness, bulbar dysfunction, and axial and limb hypotonia. [provided by RefSeq, Jul 2012]

SLC52A2 Gene-Disease associations (from GenCC):

Brown-Vialetto-van Laere syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

SLC52A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056131214).

BP6

Variant 8-144356181-G-A is Benign according to our data. Variant chr8-144356181-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2356346.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL6	NM_012162.4 link	c.1259C>T	p.Thr420Met	missense_variant	Exon 8 of 9	ENST00000331890.6	NP_036294.2	Q8N531-1
FBXL6	NM_024555.6 link	c.1241C>T	p.Thr414Met	missense_variant	Exon 8 of 9		NP_078831.4	Q8N531-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL6	ENST00000331890.6 link	c.1259C>T	p.Thr420Met	missense_variant	Exon 8 of 9	1	NM_012162.4	ENSP00000330098.5		Q8N531-1

Frequencies

GnomAD3 genomes

AF:

0.00000797

AC:

AN:

125394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000295

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250212

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1426110

Hom.:

Cov.:

AF XY:

0.0000366

AC XY:

AN XY:

709444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32534

American (AMR)

AF:

0.0000463

AC:

AN:

43220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25144

East Asian (EAS)

AF:

0.0000583

AC:

AN:

34282

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000384

AC:

AN:

1092668

Other (OTH)

AF:

0.0000690

AC:

AN:

57936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000797

AC:

AN:

125394

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60898

show subpopulations

African (AFR)

AF:

0.0000295

AC:

AN:

33952

American (AMR)

AF:

0.00

AC:

AN:

11570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3030

East Asian (EAS)

AF:

0.00

AC:

AN:

3612

South Asian (SAS)

AF:

0.00

AC:

AN:

3580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58496

Other (OTH)

AF:

0.00

AC:

AN:

1706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 03, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.5

(source)

DANN

Benign

0.85

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.014

M_CAP

Benign

0.0040

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.69

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.83

N;N

REVEL

Benign

0.010

Sift

Benign

0.21

T;T

Sift4G

Benign

0.32

T;T

Vest4

0.14

MutPred

0.30

.;Loss of phosphorylation at T420 (P = 0.0418);

MVP

0.22

MPC

0.043

ClinPred

0.010

GERP RS

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.32

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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8-144356181-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over