rs80356506

Positions:

• chr3-58077235-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001457.4(FLNB):​c.482T>G​(p.Phe161Cys) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 8.02

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 11 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
• 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, 0.992
• PP5: Variant 3-58077235-T-G is Pathogenic according to our data. Variant chr3-58077235-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-58077235-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNB	NM_001457.4	c.482T>G	p.Phe161Cys	missense_variant	2/46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.482T>G	p.Phe161Cys	missense_variant	2/47		NP_001157789.1
FLNB	NM_001164318.2	c.482T>G	p.Phe161Cys	missense_variant	2/46		NP_001157790.1
FLNB	NM_001164319.2	c.482T>G	p.Phe161Cys	missense_variant	2/45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.482T>G	p.Phe161Cys	missense_variant	2/46	1	NM_001457.4	ENSP00000295956	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Larsen syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Connective tissue disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.99
MutPred		0.91		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.97

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: rs80356506; hg19: chr3-58062962;