rs80356508

Variant names:

• chr3-58081668-G-A
• rs80356508
• NM_001457.4:c.679G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001457.4(FLNB):​c.679G>A​(p.Glu227Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.95

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Calponin-homology (CH) 2 (size 103) in uniprot entity FLNB_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_001457.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 3-58081668-G-A is Pathogenic according to our data. Variant chr3-58081668-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58081668-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.679G>A	p.Glu227Lys	missense_variant	Exon 4 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.679G>A	p.Glu227Lys	missense_variant	Exon 4 of 47		NP_001157789.1
FLNB	NM_001164318.2	c.679G>A	p.Glu227Lys	missense_variant	Exon 4 of 46		NP_001157790.1
FLNB	NM_001164319.2	c.679G>A	p.Glu227Lys	missense_variant	Exon 4 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.679G>A	p.Glu227Lys	missense_variant	Exon 4 of 46	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 227 of the FLNB protein (p.Glu227Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Larsen syndrome (PMID: 14991055, 16648377, 16801345). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6405). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FLNB protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects FLNB function (PMID: 21620354, 22190451, 26491051). For these reasons, this variant has been classified as Pathogenic. -

Sep 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect due to a defect in the CH2 domain regulatory function resulting from increased binding of the protein to F-actin or the actin cystoskeleton (Daniel et al., 2012; Zhao et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18322662, 19773341, 22190451, 16801345, 16648377, 30916490, 36267862, 33255942, 33195260, 14991055, 26491051) -

Mar 01, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Larsen syndrome Pathogenic:1 Other:1

Feb 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

FLNB-related disorder Pathogenic:1

Jun 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FLNB c.679G>A variant is predicted to result in the amino acid substitution p.Glu227Lys. This variant has been reported to be pathogenic for autosomal dominant Larsen syndrome (Krakow et al. 2004. PubMed ID: 14991055; Bicknell et al. 2007. PubMed ID: 16801345; Zhang et al. 2006. PubMed ID: 16648377; Kodra et al. 2019. PubMed ID: 30916490). Functional studies suggest that the p.Glu227Lys variant may affect cytoskeletal reorganization (Zhao et al. 2016. PubMed ID: 26491051). In addition, this variant has not been reported in a large population based variant database, indicating it is rare This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;D;D;.;D
Vest4		0.94
MutPred		0.80		Gain of ubiquitination at E227 (P = 0.0162);Gain of ubiquitination at E227 (P = 0.0162);Gain of ubiquitination at E227 (P = 0.0162);Gain of ubiquitination at E227 (P = 0.0162);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.98

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: rs80356508; hg19: chr3-58067395;