rs1553698619

Positions:

• chr3-58110018-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001457.4(FLNB):​c.2332A>G​(p.Ser778Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.35381716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNB	NM_001457.4	c.2332A>G	p.Ser778Gly	missense_variant	16/46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.2332A>G	p.Ser778Gly	missense_variant	16/47		NP_001157789.1
FLNB	NM_001164318.2	c.2332A>G	p.Ser778Gly	missense_variant	16/46		NP_001157790.1
FLNB	NM_001164319.2	c.2332A>G	p.Ser778Gly	missense_variant	16/45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.2332A>G	p.Ser778Gly	missense_variant	16/46	1	NM_001457.4	ENSP00000295956	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe postnatal growth retardation;C4024577:Synostosis involving bones of the lower limbs Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Nov 07, 2017

This variant was identified in an adult patient with severe growth delay, bilateral coxofemoral synostosis and multiple enteropathies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Benign	1.9	L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Benign	0.11	T;T;T;T;T
Sift4G	Benign	0.088	T;T;T;T;T
Polyphen		0.0050, 0.0040	.;B;B;.;B
Vest4		0.35
MutPred		0.51		Gain of catalytic residue at S778 (P = 0.0394);Gain of catalytic residue at S778 (P = 0.0394);Gain of catalytic residue at S778 (P = 0.0394);Gain of catalytic residue at S778 (P = 0.0394);.;
MVP		0.85
MPC		0.25
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.46
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553698619; hg19: chr3-58095745; COSMIC: COSV55887526;