rs147846832

Positions:

chr3-58077115-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_001457.4(FLNB):c.362A>T(p.Tyr121Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

FLNB
NM_001457.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 9.32

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 links:

FLNB (HGNC:):

FLNB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a region_of_interest Actin-binding (size 238) in uniprot entity FLNB_HUMAN there are 38 pathogenic changes around while only 1 benign (97%) in NM_001457.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNB. . Gene score misZ 2.1406 (greater than the threshold 3.09). Trascript score misZ 4.529 (greater than threshold 3.09). GenCC has associacion of gene with spondylocarpotarsal synostosis syndrome, atelosteogenesis type I, Larsen syndrome, Boomerang dysplasia, atelosteogenesis type III.

BP4

Computational evidence support a benign effect (MetaRNN=0.014203131).

BP6

Variant 3-58077115-A-T is Benign according to our data. Variant chr3-58077115-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258107.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00249 (379/152034) while in subpopulation AFR AF= 0.00875 (363/41466). AF 95% confidence interval is 0.00801. There are 4 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNB	NM_001457.4 linkuse as main transcript	c.362A>T	p.Tyr121Phe	missense_variant	2/46	ENST00000295956.9	NP_001448.2	O75369-1
FLNB	NM_001164317.2 linkuse as main transcript	c.362A>T	p.Tyr121Phe	missense_variant	2/47		NP_001157789.1	O75369-8
FLNB	NM_001164318.2 linkuse as main transcript	c.362A>T	p.Tyr121Phe	missense_variant	2/46		NP_001157790.1	O75369-9
FLNB	NM_001164319.2 linkuse as main transcript	c.362A>T	p.Tyr121Phe	missense_variant	2/45		NP_001157791.1	O75369-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9 linkuse as main transcript	c.362A>T	p.Tyr121Phe	missense_variant	2/46	1	NM_001457.4	ENSP00000295956.5		O75369-1

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00878

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000601

AC:

151

AN:

251306

Hom.:

AF XY:

0.000434

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00892

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000225

AC:

329

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

134

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00869

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00249

AC:

379

AN:

152034

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00875

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000692

Hom.:

Bravo

AF:

0.00281

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000774

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

.;D;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.76

N;N;N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Uncertain

0.024

D;D;D;D

Polyphen

1.0, 1.0

.;D;D;.

Vest4

0.57

MVP

0.89

MPC

1.9

ClinPred

0.052

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over