rs80356517

Positions:

• chr3-58108461-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001457.4(FLNB):​c.1945C>T​(p.Arg649Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FLNB NM_001457.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.77

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-58108461-C-T is Pathogenic according to our data. Variant chr3-58108461-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58108461-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNB	NM_001457.4	c.1945C>T	p.Arg649Ter	stop_gained	13/46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.1945C>T	p.Arg649Ter	stop_gained	13/47		NP_001157789.1
FLNB	NM_001164318.2	c.1945C>T	p.Arg649Ter	stop_gained	13/46		NP_001157790.1
FLNB	NM_001164319.2	c.1945C>T	p.Arg649Ter	stop_gained	13/45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.1945C>T	p.Arg649Ter	stop_gained	13/46	1	NM_001457.4	ENSP00000295956	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251084 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135702

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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456730 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725008

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: 0.0000374

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocarpotarsal synostosis syndrome Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	Feb 01, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 27, 2019	- -

FLNB-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Nov 03, 2022

The c.1945C>T;p.Arg649* variant creates a premature translational stop signal in the FLNB gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 21280; PMID: 26380986) - PS4. The variant is present at low allele frequencies population databases (rs80356517 – gnomAD 0.00003983%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
Vest4		0.84
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs80356517; hg19: chr3-58094188; COSMIC: COSV55897351;