NM_001457.4:c.4173A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001457.4(FLNB):c.4173A>G(p.Ala1391Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,612,038 control chromosomes in the GnomAD database, including 366,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41517 hom., cov: 31)

Exomes 𝑓: 0.66 ( 325177 hom. )

Consequence

FLNB
NM_001457.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.252

Publications

26 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 3-58126713-A-G is Benign according to our data. Variant chr3-58126713-A-G is described in ClinVar as Benign. ClinVar VariationId is 258110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.252 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4 link	c.4173A>G	p.Ala1391Ala	synonymous_variant	Exon 24 of 46	ENST00000295956.9	NP_001448.2	O75369-1
FLNB	NM_001164317.2 link	c.4173A>G	p.Ala1391Ala	synonymous_variant	Exon 24 of 47		NP_001157789.1	O75369-8
FLNB	NM_001164318.2 link	c.4173A>G	p.Ala1391Ala	synonymous_variant	Exon 24 of 46		NP_001157790.1	O75369-9
FLNB	NM_001164319.2 link	c.4173A>G	p.Ala1391Ala	synonymous_variant	Exon 24 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.4173A>G	p.Ala1391Ala	synonymous_variant	Exon 24 of 46	1	NM_001457.4	ENSP00000295956.5		O75369-1

Frequencies

GnomAD3 genomes

AF:

0.728

AC:

110523

AN:

151892

Hom.:

41454

Cov.:

show subpopulations

Gnomad AFR

AF:

0.894

Gnomad AMI

AF:

0.638

Gnomad AMR

AF:

0.719

Gnomad ASJ

AF:

0.659

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.781

Gnomad FIN

AF:

0.589

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.631

Gnomad OTH

AF:

0.711

GnomAD2 exomes

AF:

0.707

AC:

177678

AN:

251412

AF XY:

0.699

show subpopulations

Gnomad AFR exome

AF:

0.904

Gnomad AMR exome

AF:

0.774

Gnomad ASJ exome

AF:

0.661

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.589

Gnomad NFE exome

AF:

0.626

Gnomad OTH exome

AF:

0.681

GnomAD4 exome

AF:

0.662

AC:

966804

AN:

1460028

Hom.:

325177

Cov.:

AF XY:

0.663

AC XY:

481759

AN XY:

726522

show subpopulations

African (AFR)

AF:

0.906

AC:

30316

AN:

33450

American (AMR)

AF:

0.768

AC:

34360

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.660

AC:

17247

AN:

26122

East Asian (EAS)

AF:

0.999

AC:

39658

AN:

39698

South Asian (SAS)

AF:

0.751

AC:

64746

AN:

86218

European-Finnish (FIN)

AF:

0.589

AC:

31437

AN:

53414

Middle Eastern (MID)

AF:

0.685

AC:

3946

AN:

5758

European-Non Finnish (NFE)

AF:

0.633

AC:

703102

AN:

1110304

Other (OTH)

AF:

0.696

AC:

41992

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

15648

31296

46943

62591

78239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18870

37740

56610

75480

94350

<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:

0.728

AC:

110645

AN:

152010

Hom.:

41517

Cov.:

AF XY:

0.731

AC XY:

54323

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.895

AC:

37097

AN:

41468

American (AMR)

AF:

0.720

AC:

10984

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.659

AC:

2284

AN:

3468

East Asian (EAS)

AF:

0.997

AC:

5156

AN:

5170

South Asian (SAS)

AF:

0.780

AC:

3756

AN:

4814

European-Finnish (FIN)

AF:

0.589

AC:

6197

AN:

10522

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.631

AC:

42886

AN:

67984

Other (OTH)

AF:

0.715

AC:

1511

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1423

2846

4270

5693

7116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.672

Hom.:

26891

Bravo

AF:

0.746

EpiCase

AF:

0.640

EpiControl

AF:

0.637

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.3

(source)

DANN

Benign

0.60

PhyloP100

-0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

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