rs1131356

chr3-58123435-G-Achr3-58123435-G-Cchr3-58123435-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001457.4(FLNB):c.3469G>A(p.Asp1157Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,611,670 control chromosomes in the GnomAD database, including 87,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10746 hom., cov: 31)
  • Exomes 𝑓: 0.29 (76813 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNB
• BP4: Computational evidence support a benign effect (MetaRNN=3.0217143E-6).
• BP6: Variant 3-58123435-G-A is Benign according to our data. Variant chr3-58123435-G-A is described in ClinVar as [Benign]. Clinvar id is 258106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58123435-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.3469G>A	p.Asp1157Asn	missense_variant	21/46	ENST00000295956.9
FLNB	NM_001164317.2	c.3469G>A	p.Asp1157Asn	missense_variant	21/47
FLNB	NM_001164318.2	c.3469G>A	p.Asp1157Asn	missense_variant	21/46
FLNB	NM_001164319.2	c.3469G>A	p.Asp1157Asn	missense_variant	21/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.3469G>A	p.Asp1157Asn	missense_variant	21/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52646 AN: 151750 Hom.: 10738 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.912

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.354

GnomAD3 exomes AF: 0.377 AC: 94415 AN: 250612 Hom.: 22744 AF XY: 0.369 AC XY: 49962 AN XY: 135424

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.916

Gnomad SAS exome AF: 0.473

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.295 AC: 430524 AN: 1459802 Hom.: 76813 Cov.: 46 AF XY: 0.298 AC XY: 216218 AN XY: 725802

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.926

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.347 AC: 52686 AN: 151868 Hom.: 10746 Cov.: 31 AF XY: 0.356 AC XY: 26440 AN XY: 74238

Gnomad4 AFR AF: 0.415

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.912

Gnomad4 SAS AF: 0.526

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.355

Alfa AF: 0.288 Hom.: 12315

Bravo AF: 0.363

TwinsUK AF: 0.236 AC: 876

ALSPAC AF: 0.254 AC: 978

ESP6500AA AF: 0.411 AC: 1813

ESP6500EA AF: 0.244 AC: 2097

ExAC AF: 0.372 AC: 45152

Asia WGS AF: 0.709 AC: 2464 AN: 3478

EpiCase AF: 0.249

EpiControl AF: 0.251

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2016	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

FLNB-Related Spectrum Disorders Benign:1

Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
MetaRNN	Benign	0.0000030	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.
MutationTaster	Benign	6.2e-8	P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Benign	0.056	T;T;T;T;T
Sift4G	Uncertain	0.051	T;T;T;T;T
Polyphen		1.0, 1.0	.;D;D;.;D
Vest4		0.78
MPC		0.89
ClinPred		0.027	T
GERP RS		5.1
Varity_R		0.31
gMVP		0.80

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

Other links and lift over

dbSNP: rs1131356; hg19: chr3-58109162; COSMIC: COSV55871769;