3-58126597-T-G

Variant names:

• chr3-58126597-T-G
• rs3732632
• NM_001457.4:c.4062-5T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001457.4(FLNB):​c.4062-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,613,830 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (98 hom.)
• Consequence: FLNB NM_001457.4 splice_region, intron
• Scores: Splicing: ADA: 0.002555
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.386

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-58126597-T-G is Benign according to our data. Variant chr3-58126597-T-G is described in ClinVar as [Benign]. Clinvar id is 258109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-58126597-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.4062-5T>G		splice_region_variant, intron_variant	Intron 23 of 45	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.4062-5T>G		splice_region_variant, intron_variant	Intron 23 of 46		NP_001157789.1
FLNB	NM_001164318.2	c.4062-5T>G		splice_region_variant, intron_variant	Intron 23 of 45		NP_001157790.1
FLNB	NM_001164319.2	c.4062-5T>G		splice_region_variant, intron_variant	Intron 23 of 44		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.4062-5T>G		splice_region_variant, intron_variant	Intron 23 of 45	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1900 AN: 152132 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00882 AC: 2217 AN: 251418 Hom.: 43 AF XY: 0.00804 AC XY: 1092 AN XY: 135890

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0578

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00362 AC: 5297 AN: 1461580 Hom.: 98 Cov.: 32 AF XY: 0.00367 AC XY: 2671 AN XY: 727120

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.0538

Gnomad4 SAS exome AF: 0.00936

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.00760

GnomAD4 genome AF: 0.0126 AC: 1911 AN: 152250 Hom.: 39 Cov.: 32 AF XY: 0.0125 AC XY: 931 AN XY: 74450

Gnomad4 AFR AF: 0.0328

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0594

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00315 Hom.: 8

Bravo AF: 0.0132

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 17, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FLNB-Related Spectrum Disorders Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.1
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.090		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: rs3732632; hg19: chr3-58112324;