rs145036794

Variant names:

• chr3-58094856-A-G
• rs145036794
• NM_001457.4:c.808A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001457.4(FLNB):​c.808A>G​(p.Met270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 2.63
• Publications: 8 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019293815).
• BP6: Variant 3-58094856-A-G is Benign according to our data. Variant chr3-58094856-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252548.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000932 (142/152292) while in subpopulation NFE AF = 0.00144 (98/68020). AF 95% confidence interval is 0.00121. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.808A>G	p.Met270Val	missense	Exon 5 of 46	NP_001448.2	O75369-1
	FLNB	NM_001164317.2		c.808A>G	p.Met270Val	missense	Exon 5 of 47	NP_001157789.1	O75369-8
	FLNB	NM_001164318.2		c.808A>G	p.Met270Val	missense	Exon 5 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.808A>G	p.Met270Val	missense	Exon 5 of 46	ENSP00000295956.5	O75369-1
	FLNB	ENST00000490882.5	TSL:1	c.808A>G	p.Met270Val	missense	Exon 5 of 47	ENSP00000420213.1	O75369-8
	FLNB	ENST00000429972.6	TSL:1	c.808A>G	p.Met270Val	missense	Exon 5 of 46	ENSP00000415599.2	O75369-9

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000716 AC: 180 AN: 251378 AF XY: 0.000721

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00118 AC: 1722 AN: 1461836 Hom.: 1 Cov.: 31 AF XY: 0.00114 AC XY: 830 AN XY: 727228

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00143 AC: 1585 AN: 1111960

Other (OTH) AF: 0.00113 AC: 68 AN: 60396

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74476

African (AFR) AF: 0.000602 AC: 25 AN: 41554

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000824

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.00131

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	-	Connective tissue disorder (1)
-	1	-	FLNB-Related Spectrum Disorders (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Larsen syndrome;C0265283:Atelosteogenesis type I;C0432201:Boomerang dysplasia;C1848934:Spondylocarpotarsal synostosis syndrome;C3668942:Atelosteogenesis type III (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.32	N
PhyloP100		2.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.23
Sift	Benign	0.38	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.76
MPC		0.26
ClinPred		0.038	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.47
Mutation Taster		=82/18	polymorphism

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: rs145036794; hg19: chr3-58080583; COSMIC: COSV99913495;