NM_001457.4:c.1611-4G>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.1611-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 1,613,978 control chromosomes in the GnomAD database, including 3,403 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 (★★).

Frequency

Genomes: 𝑓 0.041 ( 172 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3231 hom. )

Consequence

FLNB
NM_001457.4 splice_region, intron

Scores

Splicing: ADA: 0.00004395

Clinical Significance

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

Conservation

PhyloP100: -0.365

Publications

3 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 (BayesDel_noAF=-0.72).

BP6

Variant 3-58105076-G-A is Benign according to our data. Variant chr3-58105076-G-A is described in ClinVar as [Benign]. Clinvar id is 258099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4 link	c.1611-4G>A	splice_region_variant, intron_variant	Intron 10 of 45	ENST00000295956.9	NP_001448.2	O75369-1
FLNB	NM_001164317.2 link	c.1611-4G>A	splice_region_variant, intron_variant	Intron 10 of 46		NP_001157789.1	O75369-8
FLNB	NM_001164318.2 link	c.1611-4G>A	splice_region_variant, intron_variant	Intron 10 of 45		NP_001157790.1	O75369-9
FLNB	NM_001164319.2 link	c.1611-4G>A	splice_region_variant, intron_variant	Intron 10 of 44		NP_001157791.1	O75369-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9 link	c.1611-4G>A		splice_region_variant, intron_variant	Intron 10 of 45	1	NM_001457.4	ENSP00000295956.5		O75369-1

Frequencies

GnomAD3 genomes

AF:

0.0410

AC:

6242

AN:

152184

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0755

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0406

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0652

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0445

AC:

11200

AN:

251480

AF XY:

0.0455

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.0224

Gnomad ASJ exome

AF:

0.0633

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0432

Gnomad NFE exome

AF:

0.0638

Gnomad OTH exome

AF:

0.0567

GnomAD4 exome

AF:

0.0619

AC:

90538

AN:

1461676

Hom.:

3231

Cov.:

AF XY:

0.0610

AC XY:

44348

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0101

AC:

337

AN:

33480

American (AMR)

AF:

0.0241

AC:

1079

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0686

AC:

1792

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0352

AC:

3036

AN:

86252

European-Finnish (FIN)

AF:

0.0435

AC:

2322

AN:

53416

Middle Eastern (MID)

AF:

0.0567

AC:

327

AN:

5768

European-Non Finnish (NFE)

AF:

0.0704

AC:

78284

AN:

1111814

Other (OTH)

AF:

0.0556

AC:

3358

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

4481

8962

13443

17924

22405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2934

5868

8802

11736

14670

<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:

0.0410

AC:

6242

AN:

152302

Hom.:

172

Cov.:

AF XY:

0.0394

AC XY:

2932

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0128

AC:

531

AN:

41564

American (AMR)

AF:

0.0229

AC:

351

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

262

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0274

AC:

132

AN:

4826

European-Finnish (FIN)

AF:

0.0406

AC:

431

AN:

10606

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0652

AC:

4437

AN:

68034

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

318

636

953

1271

1589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0582

Hom.:

242

Bravo

AF:

0.0388

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0608

EpiControl

AF:

0.0650

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 07, 2023

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jun 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. -

PreventionGenetics, part of Exact Sciences

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. -

Connective tissue disorder

Benign:1

Jun 03, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

4.0

(source)

DANN

Benign

0.60

PhyloP100

-0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over