3-58124464-C-T

Variant names:

• chr3-58124464-C-T
• rs62621997
• NM_001457.4:c.3857C>T

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.3857C>T​(p.Ala1286Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,614,142 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1286S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (192 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (214 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77
• Publications: 6 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=0.003178686).
• BP6: Variant 3-58124464-C-T is Benign according to our data. Variant chr3-58124464-C-T is described in ClinVar as Benign. ClinVar VariationId is 258108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0918 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.3857C>T	p.Ala1286Val	missense	Exon 22 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.3857C>T	p.Ala1286Val	missense	Exon 22 of 47	NP_001157789.1	O75369-8
	FLNB	NM_001164318.2		c.3857C>T	p.Ala1286Val	missense	Exon 22 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.3857C>T	p.Ala1286Val	missense	Exon 22 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.3857C>T	p.Ala1286Val	missense	Exon 22 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.3857C>T	p.Ala1286Val	missense	Exon 22 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4134 AN: 152164 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00739 AC: 1858 AN: 251472 AF XY: 0.00532

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00295 AC: 4306 AN: 1461860 Hom.: 214 Cov.: 32 AF XY: 0.00248 AC XY: 1803 AN XY: 727232

African (AFR) AF: 0.106 AC: 3538 AN: 33474

American (AMR) AF: 0.00510 AC: 228 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5764

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111994

Other (OTH) AF: 0.00697 AC: 421 AN: 60396

GnomAD4 genome AF: 0.0272 AC: 4149 AN: 152282 Hom.: 192 Cov.: 32 AF XY: 0.0270 AC XY: 2012 AN XY: 74466

African (AFR) AF: 0.0943 AC: 3918 AN: 41548

American (AMR) AF: 0.0114 AC: 175 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.00823 Hom.: 186

Bravo AF: 0.0316

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0953 AC: 420

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00905 AC: 1099

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

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	Connective tissue disorder (1)
-	-	1	FLNB-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.028	D
Polyphen		0.97	D
Vest4		0.36
MVP		0.95
MPC		0.33
ClinPred		0.015	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.36
Mutation Taster		=96/4	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: rs62621997; hg19: chr3-58110191;