rs8640

chr3-58168600-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001457.4(FLNB):c.7359C>T(p.Ser2453=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,613,232 control chromosomes in the GnomAD database, including 95,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12694 hom., cov: 33)
  • Exomes 𝑓: 0.31 (82433 hom.)
• Consequence: FLNB NM_001457.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.06

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-AS1 (HGNC:40239): (FLNB antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-58168600-C-T is Benign according to our data. Variant chr3-58168600-C-T is described in ClinVar as [Benign]. Clinvar id is 258122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58168600-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.7359C>T	p.Ser2453=	synonymous_variant	44/46	ENST00000295956.9
FLNB-AS1	NR_135534.1	n.139+1897G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.7359C>T	p.Ser2453=	synonymous_variant	44/46	1	NM_001457.4	A1
FLNB-AS1	ENST00000488720.1	n.140+1897G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57258 AN: 151918 Hom.: 12678 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.352

GnomAD3 exomes AF: 0.387 AC: 97186 AN: 251398 Hom.: 23757 AF XY: 0.378 AC XY: 51330 AN XY: 135880

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.918

Gnomad SAS exome AF: 0.485

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.307 AC: 448303 AN: 1461196 Hom.: 82433 Cov.: 36 AF XY: 0.309 AC XY: 224898 AN XY: 726922

Gnomad4 AFR exome AF: 0.522

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.928

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.338

GnomAD4 genome AF: 0.377 AC: 57319 AN: 152036 Hom.: 12694 Cov.: 33 AF XY: 0.385 AC XY: 28593 AN XY: 74314

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.913

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.354

Alfa AF: 0.300 Hom.: 4174

Bravo AF: 0.396

Asia WGS AF: 0.719 AC: 2499 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

FLNB-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.4
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs8640; hg19: chr3-58154327; COSMIC: COSV55869043; COSMIC: COSV55869043;