chr3-58126597-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

2
Splicing: ADA: 0.002555
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.386

Publications

5 publications found
Variant links:
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 Gene-Disease associations (from GenCC):
  • atelosteogenesis type I
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • atelosteogenesis type III
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • Larsen syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • spondylocarpotarsal synostosis syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
  • Boomerang dysplasia
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 258109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
FLNBNM_001457.4 linkc.4062-5T>G splice_region_variant, intron_variant Intron 23 of 45 ENST00000295956.9 NP_001448.2 O75369-1
FLNBNM_001164317.2 linkc.4062-5T>G splice_region_variant, intron_variant Intron 23 of 46 NP_001157789.1 O75369-8
FLNBNM_001164318.2 linkc.4062-5T>G splice_region_variant, intron_variant Intron 23 of 45 NP_001157790.1 O75369-9
FLNBNM_001164319.2 linkc.4062-5T>G splice_region_variant, intron_variant Intron 23 of 44 NP_001157791.1 O75369-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNBENST00000295956.9 linkc.4062-5T>G splice_region_variant, intron_variant Intron 23 of 45 1 NM_001457.4 ENSP00000295956.5 O75369-1

Frequencies

GnomAD3 genomes
AF:
0.0125
AC:
1900
AN:
152132
Hom.:
39
Cov.:
32
show subpopulations
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
GnomAD2 exomes
AF:
0.00882
AC:
2217
AN:
251418
AF XY:
0.00804
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.0322
AC:
1078
AN:
33458
American (AMR)
AF:
0.00282
AC:
126
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00402
AC:
105
AN:
26136
East Asian (EAS)
AF:
0.0538
AC:
2135
AN:
39692
South Asian (SAS)
AF:
0.00936
AC:
807
AN:
86246
European-Finnish (FIN)
AF:
0.00543
AC:
290
AN:
53418
Middle Eastern (MID)
AF:
0.00193
AC:
11
AN:
5708
European-Non Finnish (NFE)
AF:
0.000257
AC:
286
AN:
1111832
Other (OTH)
AF:
0.00760
AC:
459
AN:
60366
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.467
Heterozygous variant carriers
0
245
490
736
981
1226
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
88
176
264
352
440
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0126
AC:
1911
AN:
152250
Hom.:
39
Cov.:
32
AF XY:
0.0125
AC XY:
931
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.0328
AC:
1360
AN:
41524
American (AMR)
AF:
0.00458
AC:
70
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00288
AC:
10
AN:
3468
East Asian (EAS)
AF:
0.0594
AC:
308
AN:
5186
South Asian (SAS)
AF:
0.0125
AC:
60
AN:
4818
European-Finnish (FIN)
AF:
0.00471
AC:
50
AN:
10612
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.000485
AC:
33
AN:
68020
Other (OTH)
AF:
0.00898
AC:
19
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
87
174
261
348
435
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
24
48
72
96
120
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00471
Hom.:
24
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
LINK: link

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
Aug 26, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
PhyloP100
0.39
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs3732632; hg19: chr3-58112324; API