chr3-58106851-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001457.4(FLNB):c.1919C>T(p.Thr640Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,808 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T640T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 22 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 36 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.46

Publications

8 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:

ENSG00000303089 (HGNC:):

ENSG00000303089 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 (MetaRNN=0.0042644143).

BP6

Variant 3-58106851-C-T is Benign according to our data. Variant chr3-58106851-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 346316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00868 (1322/152274) while in subpopulation AFR AF = 0.0302 (1255/41536). AF 95% confidence interval is 0.0288. There are 22 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4 link	c.1919C>T	p.Thr640Met	missense_variant	Exon 12 of 46	ENST00000295956.9	NP_001448.2	O75369-1
FLNB	NM_001164317.2 link	c.1919C>T	p.Thr640Met	missense_variant	Exon 12 of 47		NP_001157789.1	O75369-8
FLNB	NM_001164318.2 link	c.1919C>T	p.Thr640Met	missense_variant	Exon 12 of 46		NP_001157790.1	O75369-9
FLNB	NM_001164319.2 link	c.1919C>T	p.Thr640Met	missense_variant	Exon 12 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.1919C>T	p.Thr640Met	missense_variant	Exon 12 of 46	1	NM_001457.4	ENSP00000295956.5		O75369-1

Frequencies

GnomAD3 genomes

AF:

0.00864

AC:

1315

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00261

AC:

654

AN:

250730

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00124

AC:

1813

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

831

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.0341

AC:

1142

AN:

33470

American (AMR)

AF:

0.00418

AC:

187

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000151

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00287

AC:

AN:

5572

European-Non Finnish (NFE)

AF:

0.000238

AC:

265

AN:

1111926

Other (OTH)

AF:

0.00311

AC:

188

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

170

255

340

425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00868

AC:

1322

AN:

152274

Hom.:

Cov.:

AF XY:

0.00851

AC XY:

634

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0302

AC:

1255

AN:

41536

American (AMR)

AF:

0.00242

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68016

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

130

196

261

326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00367

Hom.:

Bravo

AF:

0.0103

ESP6500AA

AF:

0.0263

AC:

116

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00289

AC:

351

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2024

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 09, 2017

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. -

FLNB-Related Spectrum Disorders

Benign:1

Jan 12, 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

Feb 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Larsen syndrome;C0265283:Atelosteogenesis type I;C0432201:Boomerang dysplasia;C1848934:Spondylocarpotarsal synostosis syndrome;C3668942:Atelosteogenesis type III

Benign:1

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T;.;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.0043

T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.3

L;L;L;L;.

PhyloP100

1.5

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

N;N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.17

T;T;T;T;D

Sift4G

Benign

0.15

T;T;T;T;T

Polyphen

0.64, 0.75

.;P;P;.;P

Vest4

0.32

MVP

0.93

MPC

0.47

ClinPred

0.023

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over