rs80356520

chr3-58136126-C-Gchr3-58136126-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP2 PP3_Moderate

The NM_001457.4(FLNB):c.4819C>G(p.Arg1607Gly) variant causes a missense change. In-silico tool predicts a pathogenic 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. R1607Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001457.4
• PP2: Missense variant where missense usually causes diseases, FLNB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNB	NM_001457.4	c.4819C>G	p.Arg1607Gly	missense_variant	28/46	ENST00000295956.9
FLNB	NM_001164317.2	c.4912C>G	p.Arg1638Gly	missense_variant	29/47
FLNB	NM_001164318.2	c.4819C>G	p.Arg1607Gly	missense_variant	28/46
FLNB	NM_001164319.2	c.4819C>G	p.Arg1607Gly	missense_variant	28/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNB	ENST00000295956.9	c.4819C>G	p.Arg1607Gly	missense_variant	28/46	1	NM_001457.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461600 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.81, 0.78, 0.62	.;P;P;.;P
Vest4		0.82
MVP		0.96
MPC		0.67
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.86

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: rs80356520; hg19: chr3-58121853;