rs80356511

Positions:

• chr3-58130810-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_001457.4(FLNB):​c.4292T>G​(p.Leu1431Arg) 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. 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:1 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 Likely_pathogenic. Variant got 9 ACMG points.

• 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, 0.977
• PP5: Variant 3-58130810-T-G is Pathogenic according to our data. Variant chr3-58130810-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-58130810-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.4292T>G	p.Leu1431Arg	missense_variant	25/46	ENST00000295956.9
FLNB	NM_001164317.2	c.4292T>G	p.Leu1431Arg	missense_variant	25/47
FLNB	NM_001164318.2	c.4292T>G	p.Leu1431Arg	missense_variant	25/46
FLNB	NM_001164319.2	c.4292T>G	p.Leu1431Arg	missense_variant	25/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.4292T>G	p.Leu1431Arg	missense_variant	25/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Larsen syndrome (PMID: 16801345). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 21281). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 1431 of the FLNB protein (p.Leu1431Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Larsen syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.99, 0.98, 0.97	.;D;D;.;D
Vest4		0.72
MutPred		0.89		Gain of methylation at L1431 (P = 0.0024);Gain of methylation at L1431 (P = 0.0024);Gain of methylation at L1431 (P = 0.0024);Gain of methylation at L1431 (P = 0.0024);.;
MVP		0.95
MPC		0.81
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.83

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: rs80356511; hg19: chr3-58116537;