3-58132828-G-A

Variant names:

• chr3-58132828-G-A
• rs12632456
• NM_001457.4:c.4411G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001457.4(FLNB):​c.4411G>A​(p.Val1471Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,613,678 control chromosomes in the GnomAD database, including 98,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1471L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (14932 hom., cov: 32)
  • Exomes 𝑓: 0.30 (83621 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.04
• Publications: 53 publications found

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), Orphanet, G2P
• atelosteogenesis type III

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Larsen syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• spondylocarpotarsal synostosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Boomerang dysplasia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.8902135E-7).
• BP6: Variant 3-58132828-G-A is Benign according to our data. Variant chr3-58132828-G-A is described in ClinVar as Benign. ClinVar VariationId is 258114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001457.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	NM_001457.4	MANE Select	c.4411G>A	p.Val1471Met	missense	Exon 26 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.4504G>A	p.Val1502Met	missense	Exon 27 of 47	NP_001157789.1	O75369-8
	FLNB	NM_001164318.2		c.4411G>A	p.Val1471Met	missense	Exon 26 of 46	NP_001157790.1	O75369-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	ENST00000295956.9	TSL:1 MANE Select	c.4411G>A	p.Val1471Met	missense	Exon 26 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.4504G>A	p.Val1502Met	missense	Exon 27 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.4411G>A	p.Val1471Met	missense	Exon 26 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60724 AN: 151894 Hom.: 14908 Cov.: 32

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.396 AC: 99624 AN: 251354 AF XY: 0.385

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.546

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.975

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.303 AC: 442578 AN: 1461666 Hom.: 83621 Cov.: 36 AF XY: 0.305 AC XY: 222113 AN XY: 727134

African (AFR) AF: 0.592 AC: 19819 AN: 33474

American (AMR) AF: 0.532 AC: 23776 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6332 AN: 26136

East Asian (EAS) AF: 0.982 AC: 39001 AN: 39698

South Asian (SAS) AF: 0.480 AC: 41406 AN: 86248

European-Finnish (FIN) AF: 0.259 AC: 13840 AN: 53406

Middle Eastern (MID) AF: 0.283 AC: 1631 AN: 5766

European-Non Finnish (NFE) AF: 0.248 AC: 275954 AN: 1111828

Other (OTH) AF: 0.345 AC: 20819 AN: 60390

GnomAD4 genome AF: 0.400 AC: 60798 AN: 152012 Hom.: 14932 Cov.: 32 AF XY: 0.408 AC XY: 30331 AN XY: 74328

African (AFR) AF: 0.589 AC: 24408 AN: 41418

American (AMR) AF: 0.456 AC: 6963 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 852 AN: 3470

East Asian (EAS) AF: 0.972 AC: 5033 AN: 5178

South Asian (SAS) AF: 0.546 AC: 2629 AN: 4812

European-Finnish (FIN) AF: 0.265 AC: 2799 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16921 AN: 67972

Other (OTH) AF: 0.394 AC: 833 AN: 2112

Alfa AF: 0.302 Hom.: 33840

Bravo AF: 0.423

TwinsUK AF: 0.238 AC: 881

ALSPAC AF: 0.255 AC: 981

ESP6500AA AF: 0.584 AC: 2573

ESP6500EA AF: 0.245 AC: 2109

ExAC AF: 0.395 AC: 47961

Asia WGS AF: 0.764 AC: 2655 AN: 3478

EpiCase AF: 0.250

EpiControl AF: 0.252

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	FLNB-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.097
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.43
Sift	Benign	0.057	T
Sift4G	Uncertain	0.047	D
Polyphen		0.81	P
Vest4		0.19
MPC		0.62
ClinPred		0.037	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.48
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12632456; hg19: chr3-58118555; COSMIC: COSV55871843;