rs12632456

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.4411G>A(p.Val1471Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,613,678 control chromosomes in the GnomAD database, including 98,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1471L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 14932 hom., cov: 32)

Exomes 𝑓: 0.30 ( 83621 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.04

Publications

53 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=8.8902135E-7).

BP6

Variant 3-58132828-G-A is Benign according to our data. Variant chr3-58132828-G-A is described in ClinVar as Benign. ClinVar VariationId is 258114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FLNB	NM_001457.4 link	c.4411G>A	p.Val1471Met	missense_variant	Exon 26 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2 link	c.4504G>A	p.Val1502Met	missense_variant	Exon 27 of 47		NP_001157789.1
FLNB	NM_001164318.2 link	c.4411G>A	p.Val1471Met	missense_variant	Exon 26 of 46		NP_001157790.1
FLNB	NM_001164319.2 link	c.4411G>A	p.Val1471Met	missense_variant	Exon 26 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9 link	c.4411G>A	p.Val1471Met	missense_variant	Exon 26 of 46	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60724

AN:

151894

Hom.:

14908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.589

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.455

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.972

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.392

GnomAD2 exomes

AF:

0.396

AC:

99624

AN:

251354

AF XY:

0.385

show subpopulations

Gnomad AFR exome

AF:

0.593

Gnomad AMR exome

AF:

0.546

Gnomad ASJ exome

AF:

0.243

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.263

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.303

AC:

442578

AN:

1461666

Hom.:

83621

Cov.:

AF XY:

0.305

AC XY:

222113

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.592

AC:

19819

AN:

33474

American (AMR)

AF:

0.532

AC:

23776

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

6332

AN:

26136

East Asian (EAS)

AF:

0.982

AC:

39001

AN:

39698

South Asian (SAS)

AF:

0.480

AC:

41406

AN:

86248

European-Finnish (FIN)

AF:

0.259

AC:

13840

AN:

53406

Middle Eastern (MID)

AF:

0.283

AC:

1631

AN:

5766

European-Non Finnish (NFE)

AF:

0.248

AC:

275954

AN:

1111828

Other (OTH)

AF:

0.345

AC:

20819

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

16774

33548

50321

67095

83869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9894

19788

29682

39576

49470

<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:

0.400

AC:

60798

AN:

152012

Hom.:

14932

Cov.:

AF XY:

0.408

AC XY:

30331

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.589

AC:

24408

AN:

41418

American (AMR)

AF:

0.456

AC:

6963

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

852

AN:

3470

East Asian (EAS)

AF:

0.972

AC:

5033

AN:

5178

South Asian (SAS)

AF:

0.546

AC:

2629

AN:

4812

European-Finnish (FIN)

AF:

0.265

AC:

2799

AN:

10570

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16921

AN:

67972

Other (OTH)

AF:

0.394

AC:

833

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1600

3199

4799

6398

7998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.302

Hom.:

33840

Bravo

AF:

0.423

TwinsUK

AF:

0.238

AC:

881

ALSPAC

AF:

0.255

AC:

981

ESP6500AA

AF:

0.584

AC:

2573

ESP6500EA

AF:

0.245

AC:

2109

ExAC

AF:

0.395

AC:

47961

Asia WGS

AF:

0.764

AC:

2655

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.252

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Apr 07, 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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D;.;.;.

Eigen

Benign

0.097

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D;D;D

MetaRNN

Benign

8.9e-7

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

.;M;M;M;.

PhyloP100

3.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.057

T;T;T;T;T

Sift4G

Uncertain

0.047

D;D;D;D;T

Polyphen

0.81, 0.88, 0.38

.;P;P;.;B

Vest4

0.19

MPC

0.62

ClinPred

0.037

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.48

Mutation Taster

=85/15

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