rs1553704446

Variant names:

• chr3-58138492-G-A
• rs1553704446
• NM_001457.4:c.5072G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001457.4(FLNB):​c.5072G>A​(p.Gly1691Asp) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1691S) 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:3
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• atelosteogenesis type I

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• atelosteogenesis type III

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Larsen syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• spondylocarpotarsal synostosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Boomerang dysplasia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-58138491-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 3-58138492-G-A is Pathogenic according to our data. Variant chr3-58138492-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.5072G>A	p.Gly1691Asp	missense_variant	Exon 29 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.5165G>A	p.Gly1722Asp	missense_variant	Exon 30 of 47		NP_001157789.1
FLNB	NM_001164318.2	c.5072G>A	p.Gly1691Asp	missense_variant	Exon 29 of 46		NP_001157790.1
FLNB	NM_001164319.2	c.5072G>A	p.Gly1691Asp	missense_variant	Exon 29 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.5072G>A	p.Gly1691Asp	missense_variant	Exon 29 of 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Abnormality of the skeletal system Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1691 of the FLNB protein (p.Gly1691Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Larsen syndrome (PMID: 22190451; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522782). 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%. This variant disrupts the p.Gly1691 amino acid residue in FLNB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14991055, 16648377, 16752402, 27048506). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Larsen syndrome Pathogenic:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	.;M;M;M;.
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	.;D;D;.;D
Vest4		0.94
MutPred		0.78		.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.97
MPC		1.0
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553704446; hg19: chr3-58124219;