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.4221C>T(p.Pro1407Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,610,188 control chromosomes in the GnomAD database, including 105,646 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1407P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 18322 hom., cov: 31)

Exomes 𝑓: 0.31 ( 87324 hom. )

Consequence

FLNB
NM_001457.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0008465

Clinical Significance

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

Conservation

PhyloP100: -0.0230

Publications

31 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=-0.53).

BP6

Variant 3-58126761-C-T is Benign according to our data. Variant chr3-58126761-C-T is described in ClinVar as Benign. ClinVar VariationId is 258111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.023 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 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
FLNB	NM_001457.4	MANE Select	c.4221C>T	p.Pro1407Pro	splice_region synonymous	Exon 24 of 46	NP_001448.2
FLNB	NM_001164317.2		c.4221C>T	p.Pro1407Pro	splice_region synonymous	Exon 24 of 47	NP_001157789.1
FLNB	NM_001164318.2		c.4221C>T	p.Pro1407Pro	splice_region synonymous	Exon 24 of 46	NP_001157790.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNB	ENST00000295956.9	TSL:1 MANE Select	c.4221C>T	p.Pro1407Pro	splice_region synonymous	Exon 24 of 46	ENSP00000295956.5
FLNB	ENST00000490882.5	TSL:1	c.4221C>T	p.Pro1407Pro	splice_region synonymous	Exon 24 of 47	ENSP00000420213.1
FLNB	ENST00000429972.6	TSL:1	c.4221C>T	p.Pro1407Pro	splice_region synonymous	Exon 24 of 46	ENSP00000415599.2

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

66050

AN:

151814

Hom.:

18285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.710

Gnomad AMI

AF:

0.309

Gnomad AMR

AF:

0.470

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.972

Gnomad SAS

AF:

0.553

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.271

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.419

GnomAD2 exomes

AF:

0.407

AC:

102132

AN:

250704

AF XY:

0.394

show subpopulations

Gnomad AFR exome

AF:

0.723

Gnomad AMR exome

AF:

0.555

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.263

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.327

GnomAD4 exome

AF:

0.307

AC:

447331

AN:

1458256

Hom.:

87324

Cov.:

AF XY:

0.309

AC XY:

224276

AN XY:

725618

show subpopulations

African (AFR)

AF:

0.726

AC:

24246

AN:

33394

American (AMR)

AF:

0.541

AC:

24187

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6336

AN:

26106

East Asian (EAS)

AF:

0.982

AC:

38993

AN:

39690

South Asian (SAS)

AF:

0.484

AC:

41709

AN:

86138

European-Finnish (FIN)

AF:

0.259

AC:

13841

AN:

53396

Middle Eastern (MID)

AF:

0.294

AC:

1691

AN:

5754

European-Non Finnish (NFE)

AF:

0.248

AC:

274943

AN:

1108832

Other (OTH)

AF:

0.355

AC:

21385

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

13490

26980

40469

53959

67449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9876

19752

29628

39504

49380

<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:

0.435

AC:

66146

AN:

151932

Hom.:

18322

Cov.:

AF XY:

0.443

AC XY:

32906

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.711

AC:

29431

AN:

41420

American (AMR)

AF:

0.471

AC:

7187

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

852

AN:

3468

East Asian (EAS)

AF:

0.972

AC:

5030

AN:

5174

South Asian (SAS)

AF:

0.552

AC:

2644

AN:

4792

European-Finnish (FIN)

AF:

0.265

AC:

2788

AN:

10530

Middle Eastern (MID)

AF:

0.277

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.250

AC:

16965

AN:

67964

Other (OTH)

AF:

0.420

AC:

887

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1495

2990

4484

5979

7474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.312

Hom.:

45069

Bravo

AF:

0.464

Asia WGS

AF:

0.774

AC:

2691

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.253

ClinVar

ClinVar submissions as Germline

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

-0.53

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

-0.023

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=66/34

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00085

dbscSNV1_RF

Benign

0.054

SpliceAI score (max)

0.010

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over