rs1470699812

Positions:

• chr3-58143561-TGAG-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001457.4(FLNB):​c.5375_5377delAGG​(p.Glu1792del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FLNB NM_001457.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U: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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001457.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-58143561-TGAG-T is Pathogenic according to our data. Variant chr3-58143561-TGAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599274.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNB	NM_001457.4	c.5375_5377delAGG	p.Glu1792del	disruptive_inframe_deletion	32/46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.5468_5470delAGG	p.Glu1823del	disruptive_inframe_deletion	33/47		NP_001157789.1
FLNB	NM_001164318.2	c.5342_5344delAGG	p.Glu1781del	disruptive_inframe_deletion	32/46		NP_001157790.1
FLNB	NM_001164319.2	c.5303_5305delAGG	p.Glu1768del	disruptive_inframe_deletion	31/45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.5375_5377delAGG	p.Glu1792del	disruptive_inframe_deletion	32/46	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2023	In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34491919, 36326072, 31836586) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This variant, c.5375_5377del, results in the deletion of 1 amino acid(s) of the FLNB protein (p.Glu1792del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with Larsen syndrome (PMID: 31836586). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Glu1823del. ClinVar contains an entry for this variant (Variation ID: 599274). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Knee dislocation;C1840068:Patellar hypoplasia;C1968606:Limited knee flexion/extension Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute for Genomic Medicine, Nationwide Children's Hospital

Dec 21, 2018

The c.5375_5377delAGG variant is a 3-bp deletion predicted to remove a highly conserved glutamic acid residue at position 1792 of the filamin B protein. This variant maps to one of numerous filamin domains in FLNB, but the local sequence context is not repetitive. Further, pathogenic mutations in two immediately adjacent filamin domains have been reported to the ClinVar database. In the gnomAD database, two out of 125,709 individuals are reported to be heterozygous for the c.5375_5377delAGG variant; however, only one of them has sequence data available for review. This variant segregates with disease in multiple affected family members. We therefore interpret it as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1470699812; hg19: chr3-58129288;