rs2140104

chr3-58106801-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001457.4(FLNB):c.1869C>T(p.Asp623=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,613,896 control chromosomes in the GnomAD database, including 1,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (157 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1532 hom.)
• Consequence: FLNB NM_001457.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.308

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-58106801-C-T is Benign according to our data. Variant chr3-58106801-C-T is described in ClinVar as [Benign]. Clinvar id is 258100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58106801-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0434 (6603/152192) while in subpopulation AFR AF= 0.0517 (2145/41522). AF 95% confidence interval is 0.0498. There are 157 homozygotes in gnomad4. There are 3130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 158 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.1869C>T	p.Asp623=	synonymous_variant	12/46	ENST00000295956.9
FLNB	NM_001164317.2	c.1869C>T	p.Asp623=	synonymous_variant	12/47
FLNB	NM_001164318.2	c.1869C>T	p.Asp623=	synonymous_variant	12/46
FLNB	NM_001164319.2	c.1869C>T	p.Asp623=	synonymous_variant	12/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.1869C>T	p.Asp623=	synonymous_variant	12/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6601 AN: 152074 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.0659

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0359 AC: 9012 AN: 251284 Hom.: 216 AF XY: 0.0363 AC XY: 4935 AN XY: 135806

Gnomad AFR exome AF: 0.0511

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0489

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0349

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0437 AC: 63841 AN: 1461704 Hom.: 1532 Cov.: 32 AF XY: 0.0431 AC XY: 31305 AN XY: 727156

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0492

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0356

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0472

Gnomad4 OTH exome AF: 0.0388

GnomAD4 genome AF: 0.0434 AC: 6603 AN: 152192 Hom.: 157 Cov.: 32 AF XY: 0.0421 AC XY: 3130 AN XY: 74400

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.0234

Gnomad4 ASJ AF: 0.0470

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0327

Gnomad4 FIN AF: 0.0361

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0481 Hom.: 108

Bravo AF: 0.0424

Asia WGS AF: 0.0240 AC: 82 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0390

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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 12, 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

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.1
Dann	Benign	0.66
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: rs2140104; hg19: chr3-58092528; COSMIC: COSV55873248;