Genetic Variant FLNB:p.Asp623Asp (chr3-58106801-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001457.4(FLNB):c.1869C>T(p.Asp623Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,613,896 control chromosomes in the GnomAD database, including 1,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 157 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1532 hom. )

Consequence

FLNB
NM_001457.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.308

Publications

10 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:

ENSG00000303089 (HGNC:):

ENSG00000303089 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=-0.47).

BP6

Variant 3-58106801-C-T is Benign according to our data. Variant chr3-58106801-C-T is described in ClinVar as Benign. ClinVar VariationId is 258100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.308 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0434 (6603/152192) while in subpopulation AFR AF = 0.0517 (2145/41522). AF 95% confidence interval is 0.0498. There are 157 homozygotes in GnomAd4. There are 3130 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 157 AD,AR gene

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.1869C>T	p.Asp623Asp	synonymous	Exon 12 of 46	NP_001448.2	O75369-1
FLNB	NM_001164317.2		c.1869C>T	p.Asp623Asp	synonymous	Exon 12 of 47	NP_001157789.1	O75369-8
FLNB	NM_001164318.2		c.1869C>T	p.Asp623Asp	synonymous	Exon 12 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.1869C>T	p.Asp623Asp	synonymous	Exon 12 of 46	ENSP00000295956.5	O75369-1
FLNB	ENST00000490882.5	TSL:1	c.1869C>T	p.Asp623Asp	synonymous	Exon 12 of 47	ENSP00000420213.1	O75369-8
FLNB	ENST00000429972.6	TSL:1	c.1869C>T	p.Asp623Asp	synonymous	Exon 12 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes

AF:

0.0434

AC:

6601

AN:

152074

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.0659

Gnomad AMR

AF:

0.0235

Gnomad ASJ

AF:

0.0470

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0329

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0481

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0359

AC:

9012

AN:

251284

AF XY:

0.0363

show subpopulations

Gnomad AFR exome

AF:

0.0511

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0489

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0410

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0308

GnomAD4 exome

AF:

0.0437

AC:

63841

AN:

1461704

Hom.:

1532

Cov.:

AF XY:

0.0431

AC XY:

31305

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0510

AC:

1706

AN:

33480

American (AMR)

AF:

0.0125

AC:

560

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0492

AC:

1286

AN:

26134

East Asian (EAS)

AF:

0.000403

AC:

AN:

39698

South Asian (SAS)

AF:

0.0356

AC:

3069

AN:

86256

European-Finnish (FIN)

AF:

0.0420

AC:

2245

AN:

53414

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0472

AC:

52518

AN:

1111850

Other (OTH)

AF:

0.0388

AC:

2343

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2998

5995

8993

11990

14988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1960

3920

5880

7840

9800

<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:

0.0434

AC:

6603

AN:

152192

Hom.:

157

Cov.:

AF XY:

0.0421

AC XY:

3130

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0517

AC:

2145

AN:

41522

American (AMR)

AF:

0.0234

AC:

358

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

163

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0327

AC:

157

AN:

4804

European-Finnish (FIN)

AF:

0.0361

AC:

383

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0481

AC:

3271

AN:

68000

Other (OTH)

AF:

0.0303

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

314

628

943

1257

1571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0456

Hom.:

163

Bravo

AF:

0.0424

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.0402

EpiControl

AF:

0.0390

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)

Connective tissue disorder (1)

FLNB-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.1

(source)

DANN

Benign

0.66

PhyloP100

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over