chr3-58123435-G-A

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.3469G>A(p.Asp1157Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,611,670 control chromosomes in the GnomAD database, including 87,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1157D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.35 ( 10746 hom., cov: 31)

Exomes 𝑓: 0.29 ( 76813 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 10.0

Publications

57 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=3.0217143E-6).

BP6

Variant 3-58123435-G-A is Benign according to our data. Variant chr3-58123435-G-A is described in ClinVar as Benign. ClinVar VariationId is 258106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4 link	c.3469G>A	p.Asp1157Asn	missense_variant	Exon 21 of 46	ENST00000295956.9	NP_001448.2	O75369-1
FLNB	NM_001164317.2 link	c.3469G>A	p.Asp1157Asn	missense_variant	Exon 21 of 47		NP_001157789.1	O75369-8
FLNB	NM_001164318.2 link	c.3469G>A	p.Asp1157Asn	missense_variant	Exon 21 of 46		NP_001157790.1	O75369-9
FLNB	NM_001164319.2 link	c.3469G>A	p.Asp1157Asn	missense_variant	Exon 21 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.3469G>A	p.Asp1157Asn	missense_variant	Exon 21 of 46	1	NM_001457.4	ENSP00000295956.5		O75369-1

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52646

AN:

151750

Hom.:

10738

Cov.:

show subpopulations

Gnomad AFR

AF:

0.416

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.438

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.912

Gnomad SAS

AF:

0.527

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.354

GnomAD2 exomes

AF:

0.377

AC:

94415

AN:

250612

AF XY:

0.369

show subpopulations

Gnomad AFR exome

AF:

0.418

Gnomad AMR exome

AF:

0.538

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.916

Gnomad FIN exome

AF:

0.260

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.308

GnomAD4 exome

AF:

0.295

AC:

430524

AN:

1459802

Hom.:

76813

Cov.:

AF XY:

0.298

AC XY:

216218

AN XY:

725802

show subpopulations

African (AFR)

AF:

0.416

AC:

13894

AN:

33428

American (AMR)

AF:

0.523

AC:

23326

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

6197

AN:

26078

East Asian (EAS)

AF:

0.926

AC:

36729

AN:

39648

South Asian (SAS)

AF:

0.463

AC:

39935

AN:

86168

European-Finnish (FIN)

AF:

0.254

AC:

13562

AN:

53348

Middle Eastern (MID)

AF:

0.267

AC:

1539

AN:

5762

European-Non Finnish (NFE)

AF:

0.248

AC:

275713

AN:

1110446

Other (OTH)

AF:

0.326

AC:

19629

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

17003

34006

51008

68011

85014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9840

19680

29520

39360

49200

<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:

0.347

AC:

52686

AN:

151868

Hom.:

10746

Cov.:

AF XY:

0.356

AC XY:

26440

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.415

AC:

17194

AN:

41392

American (AMR)

AF:

0.439

AC:

6696

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

838

AN:

3472

East Asian (EAS)

AF:

0.912

AC:

4711

AN:

5166

South Asian (SAS)

AF:

0.526

AC:

2530

AN:

4814

European-Finnish (FIN)

AF:

0.260

AC:

2745

AN:

10538

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.248

AC:

16869

AN:

67924

Other (OTH)

AF:

0.355

AC:

747

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1608

3216

4824

6432

8040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.292

Hom.:

25598

Bravo

AF:

0.363

TwinsUK

AF:

0.236

AC:

876

ALSPAC

AF:

0.254

AC:

978

ESP6500AA

AF:

0.411

AC:

1813

ESP6500EA

AF:

0.244

AC:

2097

ExAC

AF:

0.372

AC:

45152

Asia WGS

AF:

0.709

AC:

2464

AN:

3478

EpiCase

AF:

0.249

EpiControl

AF:

0.251

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 18, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 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:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0000030

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;M;M;M;.

PhyloP100

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Uncertain

0.56

Sift

Benign

0.056

T;T;T;T;T

Sift4G

Uncertain

0.051

T;T;T;T;T

Polyphen

1.0, 1.0

.;D;D;.;D

Vest4

0.78

MPC

0.89

ClinPred

0.027

GERP RS

5.1

Varity_R

0.31

gMVP

0.80

Mutation Taster

=92/8

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