3-58111800-G-T

Position:

• chr3-58111800-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001457.4(FLNB):​c.2494G>T​(p.Ala832Ser) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A832T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279

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 1 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=0.11275849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.2494G>T	p.Ala832Ser	missense_variant	17/46	ENST00000295956.9
FLNB	NM_001164317.2	c.2494G>T	p.Ala832Ser	missense_variant	17/47
FLNB	NM_001164318.2	c.2494G>T	p.Ala832Ser	missense_variant	17/46
FLNB	NM_001164319.2	c.2494G>T	p.Ala832Ser	missense_variant	17/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.2494G>T	p.Ala832Ser	missense_variant	17/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.24	.;T;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.060	N;N;N;N;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.30	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.40	T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.31, 0.27, 0.51	.;B;B;.;P
Vest4		0.11
MutPred		0.46		Gain of disorder (P = 0.0293);Gain of disorder (P = 0.0293);Gain of disorder (P = 0.0293);Gain of disorder (P = 0.0293);.;
MVP		0.69
MPC		0.40
ClinPred		0.16	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs114804033; hg19: chr3-58097527;