rs80356511

Variant names:

• chr3-58130810-T-G
• rs80356511
• NM_001457.4:c.4292T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.4292T>G	p.Leu1431Arg	missense_variant	Exon 25 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.4292T>G	p.Leu1431Arg	missense_variant	Exon 25 of 47		NP_001157789.1
FLNB	NM_001164318.2	c.4292T>G	p.Leu1431Arg	missense_variant	Exon 25 of 46		NP_001157790.1
FLNB	NM_001164319.2	c.4292T>G	p.Leu1431Arg	missense_variant	Exon 25 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.4292T>G	p.Leu1431Arg	missense_variant	Exon 25 of 46	1	NM_001457.4	ENSP00000295956.5

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

Apr 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. 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. 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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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;.
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;