Variant 3-58008665-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2

The NM_001457.4(FLNB):c.101A>G(p.Asn34Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.00

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a region_of_interest Actin-binding (size 238) in uniprot entity FLNB_HUMAN there are 58 pathogenic changes around while only 5 benign (92%) in NM_001457.4

PP2

Missense variant where missense usually causes diseases, FLNB

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FLNB	NM_001457.4 linkuse as main transcript	c.101A>G	p.Asn34Ser	missense_variant	1/46	ENST00000295956.9
FLNB	NM_001164317.2 linkuse as main transcript	c.101A>G	p.Asn34Ser	missense_variant	1/47
FLNB	NM_001164318.2 linkuse as main transcript	c.101A>G	p.Asn34Ser	missense_variant	1/46
FLNB	NM_001164319.2 linkuse as main transcript	c.101A>G	p.Asn34Ser	missense_variant	1/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9 linkuse as main transcript	c.101A>G	p.Asn34Ser	missense_variant	1/46	1	NM_001457.4	A1	O75369-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251332

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000816

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the FLNB protein (p.Asn34Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FLNB-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLNB protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

1.4

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.5

D;D;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.076

T;T;T;T

Polyphen

0.99, 0.99

.;D;D;.

Vest4

0.27

MutPred

0.44

Gain of MoRF binding (P = 0.1098);Gain of MoRF binding (P = 0.1098);Gain of MoRF binding (P = 0.1098);Gain of MoRF binding (P = 0.1098);

MVP

0.97

MPC

0.71

ClinPred

0.96

GERP RS

5.5

Varity_R

0.65

gMVP

0.30

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