rs80356507

Variant names:

• chr3-58081689-C-G
• rs80356507
• NM_001457.4:c.700C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001457.4(FLNB):​c.700C>G​(p.Leu234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. L234L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.37
• Publications: 3 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), G2P, Orphanet
• atelosteogenesis type III

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

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

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001457.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.700C>G	p.Leu234Val	missense_variant	Exon 4 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.700C>G	p.Leu234Val	missense_variant	Exon 4 of 47		NP_001157789.1
FLNB	NM_001164318.2	c.700C>G	p.Leu234Val	missense_variant	Exon 4 of 46		NP_001157790.1
FLNB	NM_001164319.2	c.700C>G	p.Leu234Val	missense_variant	Exon 4 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.700C>G	p.Leu234Val	missense_variant	Exon 4 of 46	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Larsen syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.3	L;L;L;L;.
PhyloP100		3.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.083	T;T;T;T;D
Polyphen		1.0, 0.98, 1.0	.;D;D;.;D
Vest4		0.71
MutPred		0.80		Loss of glycosylation at P238 (P = 0.0204);Loss of glycosylation at P238 (P = 0.0204);Loss of glycosylation at P238 (P = 0.0204);Loss of glycosylation at P238 (P = 0.0204);.;
MVP		0.94
MPC		1.8
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.85
gMVP		0.77
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs80356507; hg19: chr3-58067416;