NM_001457.4:c.2494G>T

Variant names:

• chr3-58111800-G-T
• rs114804033
• NM_001457.4:c.2494G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 17/22 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
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11275849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.2494G>T	p.Ala832Ser	missense_variant	Exon 17 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.2494G>T	p.Ala832Ser	missense_variant	Exon 17 of 47		NP_001157789.1
FLNB	NM_001164318.2	c.2494G>T	p.Ala832Ser	missense_variant	Exon 17 of 46		NP_001157790.1
FLNB	NM_001164319.2	c.2494G>T	p.Ala832Ser	missense_variant	Exon 17 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.2494G>T	p.Ala832Ser	missense_variant	Exon 17 of 46	1	NM_001457.4	ENSP00000295956.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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;.
PhyloP100		0.28
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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs114804033; hg19: chr3-58097527;