NM_001457.4:c.3857C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001457.4(FLNB):c.3857C>T(p.Ala1286Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,614,142 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1286S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 192 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 214 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.77

Publications

6 publications found

Variant links:

Genes affected

FLNB (HGNC:3755): (filamin B) This gene encodes a member of the filamin family. The encoded protein interacts with glycoprotein Ib alpha as part of the process to repair vascular injuries. The platelet glycoprotein Ib complex includes glycoprotein Ib alpha, and it binds the actin cytoskeleton. Mutations in this gene have been found in several conditions: atelosteogenesis type 1 and type 3; boomerang dysplasia; autosomal dominant Larsen syndrome; and spondylocarpotarsal synostosis syndrome. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Nov 2009]

FLNB Gene-Disease associations (from GenCC):

atelosteogenesis type I
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
atelosteogenesis type III
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
Larsen syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
spondylocarpotarsal synostosis syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
Boomerang dysplasia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

FLNB 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=0.003178686).

BP6

Variant 3-58124464-C-T is Benign according to our data. Variant chr3-58124464-C-T is described in ClinVar as Benign. ClinVar VariationId is 258108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4 link	c.3857C>T	p.Ala1286Val	missense_variant	Exon 22 of 46	ENST00000295956.9	NP_001448.2	O75369-1
FLNB	NM_001164317.2 link	c.3857C>T	p.Ala1286Val	missense_variant	Exon 22 of 47		NP_001157789.1	O75369-8
FLNB	NM_001164318.2 link	c.3857C>T	p.Ala1286Val	missense_variant	Exon 22 of 46		NP_001157790.1	O75369-9
FLNB	NM_001164319.2 link	c.3857C>T	p.Ala1286Val	missense_variant	Exon 22 of 45		NP_001157791.1	O75369-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9 link	c.3857C>T	p.Ala1286Val	missense_variant	Exon 22 of 46	1	NM_001457.4	ENSP00000295956.5		O75369-1

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

4134

AN:

152164

Hom.:

191

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.00739

AC:

1858

AN:

251472

AF XY:

0.00532

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.00442

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00295

AC:

4306

AN:

1461860

Hom.:

214

Cov.:

AF XY:

0.00248

AC XY:

1803

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.106

AC:

3538

AN:

33474

American (AMR)

AF:

0.00510

AC:

228

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000243

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00642

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111994

Other (OTH)

AF:

0.00697

AC:

421

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

232

465

697

930

1162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0272

AC:

4149

AN:

152282

Hom.:

192

Cov.:

AF XY:

0.0270

AC XY:

2012

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0943

AC:

3918

AN:

41548

American (AMR)

AF:

0.0114

AC:

175

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68020

Other (OTH)

AF:

0.0194

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

189

377

566

754

943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.00823

Hom.:

186

Bravo

AF:

0.0316

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0953

AC:

420

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00905

AC:

1099

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

FLNB-Related Spectrum Disorders

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder

Benign:1

Jun 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

.;D;.;.;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

D;D;D;D;D

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.6

L;L;L;L;.

PhyloP100

1.8

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.6

D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Uncertain

0.028

D;D;D;D;D

Polyphen

0.97, 0.96, 0.98

.;D;D;.;D

Vest4

0.36

MVP

0.95

MPC

0.33

ClinPred

0.015

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.36

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over