Genetic Variant FLNB:p.Ser309Ser (chr3-58096161-T-C) – ACMG Classification: Benign (-21 pts)

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.927T>C(p.Ser309Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,612,054 control chromosomes in the GnomAD database, including 135,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16734 hom., cov: 32)

Exomes 𝑓: 0.38 ( 118969 hom. )

Consequence

FLNB
NM_001457.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.88

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

FLNB links:

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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=-0.64).

BP6

Variant 3-58096161-T-C is Benign according to our data. Variant chr3-58096161-T-C is described in ClinVar as Benign. ClinVar VariationId is 258123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.88 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001457.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNB	NM_001457.4	MANE Select	c.927T>C	p.Ser309Ser	synonymous	Exon 6 of 46	NP_001448.2	O75369-1
FLNB	NM_001164317.2		c.927T>C	p.Ser309Ser	synonymous	Exon 6 of 47	NP_001157789.1	O75369-8
FLNB	NM_001164318.2		c.927T>C	p.Ser309Ser	synonymous	Exon 6 of 46	NP_001157790.1	O75369-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNB	ENST00000295956.9	TSL:1 MANE Select	c.927T>C	p.Ser309Ser	synonymous	Exon 6 of 46	ENSP00000295956.5	O75369-1
FLNB	ENST00000490882.5	TSL:1	c.927T>C	p.Ser309Ser	synonymous	Exon 6 of 47	ENSP00000420213.1	O75369-8
FLNB	ENST00000429972.6	TSL:1	c.927T>C	p.Ser309Ser	synonymous	Exon 6 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes

AF:

0.442

AC:

67188

AN:

151902

Hom.:

16709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.533

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.286

Gnomad EAS

AF:

0.975

Gnomad SAS

AF:

0.630

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.333

Gnomad OTH

AF:

0.431

GnomAD2 exomes

AF:

0.469

AC:

117670

AN:

250958

AF XY:

0.460

show subpopulations

Gnomad AFR exome

AF:

0.534

Gnomad AMR exome

AF:

0.670

Gnomad ASJ exome

AF:

0.287

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.405

GnomAD4 exome

AF:

0.379

AC:

553545

AN:

1460034

Hom.:

118969

Cov.:

AF XY:

0.383

AC XY:

278118

AN XY:

726420

show subpopulations

African (AFR)

AF:

0.534

AC:

17848

AN:

33436

American (AMR)

AF:

0.653

AC:

29179

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

7440

AN:

26112

East Asian (EAS)

AF:

0.983

AC:

39012

AN:

39696

South Asian (SAS)

AF:

0.572

AC:

49328

AN:

86216

European-Finnish (FIN)

AF:

0.357

AC:

19042

AN:

53308

Middle Eastern (MID)

AF:

0.351

AC:

2026

AN:

5766

European-Non Finnish (NFE)

AF:

0.329

AC:

364911

AN:

1110442

Other (OTH)

AF:

0.410

AC:

24759

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

15844

31688

47531

63375

79219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12212

24424

36636

48848

61060

<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:

0.442

AC:

67260

AN:

152020

Hom.:

16734

Cov.:

AF XY:

0.451

AC XY:

33514

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.533

AC:

22111

AN:

41470

American (AMR)

AF:

0.544

AC:

8322

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

993

AN:

3468

East Asian (EAS)

AF:

0.975

AC:

5036

AN:

5164

South Asian (SAS)

AF:

0.630

AC:

3030

AN:

4812

European-Finnish (FIN)

AF:

0.351

AC:

3701

AN:

10554

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.333

AC:

22615

AN:

67962

Other (OTH)

AF:

0.431

AC:

907

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1714

3429

5143

6858

8572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.353

Hom.:

3764

Bravo

AF:

0.461

Asia WGS

AF:

0.791

AC:

2750

AN:

3478

EpiCase

AF:

0.326

EpiControl

AF:

0.327

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

FLNB-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.91

(source)

DANN

Benign

0.57

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over