rs145036794

Positions:

chr3-58094856-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBP6BS1

The NM_001457.4(FLNB):c.808A>G(p.Met270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 2.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNB. . Gene score misZ 2.1406 (greater than the threshold 3.09). Trascript score misZ 4.529 (greater than threshold 3.09). GenCC has associacion of gene with spondylocarpotarsal synostosis syndrome, atelosteogenesis type I, Larsen syndrome, Boomerang dysplasia, atelosteogenesis type III.

BP4

Computational evidence support a benign effect (MetaRNN=0.019293815).

BP6

Variant 3-58094856-A-G is Benign according to our data. Variant chr3-58094856-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252548.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr3-58094856-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000932 (142/152292) while in subpopulation NFE AF= 0.00144 (98/68020). AF 95% confidence interval is 0.00121. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FLNB	NM_001457.4 linkuse as main transcript	c.808A>G	p.Met270Val	missense_variant	5/46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2 linkuse as main transcript	c.808A>G	p.Met270Val	missense_variant	5/47		NP_001157789.1
FLNB	NM_001164318.2 linkuse as main transcript	c.808A>G	p.Met270Val	missense_variant	5/46		NP_001157790.1
FLNB	NM_001164319.2 linkuse as main transcript	c.808A>G	p.Met270Val	missense_variant	5/45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9 linkuse as main transcript	c.808A>G	p.Met270Val	missense_variant	5/46	1	NM_001457.4	ENSP00000295956	A1	O75369-1

Frequencies

GnomAD3 genomes

AF:

0.000933

AC:

142

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000716

AC:

180

AN:

251378

Hom.:

AF XY:

0.000721

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00118

AC:

1722

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

830

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000932

AC:

142

AN:

152292

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.000824

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 30, 2015

- -

FLNB-Related Spectrum Disorders

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 18, 2022

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.21

.;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.043

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.019

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

-0.32

N;N;N;N;.

MutationTaster

Benign

0.70

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.050

N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.38

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0, 0.0010

.;B;B;.;B

Vest4

0.14

MVP

0.76

MPC

0.26

ClinPred

0.038

GERP RS

5.7

Varity_R

0.54

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over