rs80356504

Positions:

• chr3-58077255-G-A
• chr3-58077255-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001457.4(FLNB):​c.502G>A​(p.Gly168Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G168C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• 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]

FLNB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-58077255-G-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-58077255-G-A is Pathogenic according to our data. Variant chr3-58077255-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58077255-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-58077255-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNB	NM_001457.4	c.502G>A	p.Gly168Ser	missense_variant	2/46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.502G>A	p.Gly168Ser	missense_variant	2/47		NP_001157789.1
FLNB	NM_001164318.2	c.502G>A	p.Gly168Ser	missense_variant	2/46		NP_001157790.1
FLNB	NM_001164319.2	c.502G>A	p.Gly168Ser	missense_variant	2/45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.502G>A	p.Gly168Ser	missense_variant	2/46	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 04, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 168 of the FLNB protein (p.Gly168Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant FLNB-related conditions (PMID: 16752402, 16801345, 22190451). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 38961). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNB protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FLNB function (PMID: 26491051). -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 11, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2024

The c.502G>A (p.G168S) alteration is located in exon 2 (coding exon 2) of the FLNB gene. This alteration results from a G to A substitution at nucleotide position 502, causing the glycine (G) at amino acid position 168 to be replaced by a serine (S). for autosomal dominant FLNB-related skeletal disorders; however, its clinical significance for autosomal recessive Spondylocarpotarsal synostosis syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with FLNB-related skeletal disorders, including multiple de novo occurrences (Farrington-Rock, 2006; Bicknell, 2007; Winer, 2009; Petrovski, 2019; Daniel, 2012). Two other alterations at the same codon, c.502G>T (p.G168C) and c.503G>T (p.G168V), have been described individuals with features consistent with FLNB-related skeletal disorders (Daniel, 2012). In an assay testing FLNB function, this variant showed a functionally indeterminant result (Zhao, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

Larsen syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FLNB -related disorder (ClinVar ID: VCV000038961 / PMID: 16752402). Different missense changes at the same codon (p.Gly168Cys, p.Gly168Val) have been reported to be associated with FLNB -related disorder (ClinVar ID: VCV000812028 / PMID: 22190451). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

FLNB-related disorder Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89
MutPred		0.91		Loss of glycosylation at K169 (P = 0.1684);Loss of glycosylation at K169 (P = 0.1684);Loss of glycosylation at K169 (P = 0.1684);Loss of glycosylation at K169 (P = 0.1684);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.93

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: rs80356504; hg19: chr3-58062982;