chr3-58008645-C-G

Variant names:

• chr3-58008645-C-G
• NM_001457.4:c.81C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001457.4(FLNB):​c.81C>G​(p.Asn27Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNB NM_001457.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 238) in uniprot entity FLNB_HUMAN there are 38 pathogenic changes around while only 1 benign (97%) in NM_001457.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNB	NM_001457.4	c.81C>G	p.Asn27Lys	missense_variant	Exon 1 of 46	ENST00000295956.9	NP_001448.2
FLNB	NM_001164317.2	c.81C>G	p.Asn27Lys	missense_variant	Exon 1 of 47		NP_001157789.1
FLNB	NM_001164318.2	c.81C>G	p.Asn27Lys	missense_variant	Exon 1 of 46		NP_001157790.1
FLNB	NM_001164319.2	c.81C>G	p.Asn27Lys	missense_variant	Exon 1 of 45		NP_001157791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNB	ENST00000295956.9	c.81C>G	p.Asn27Lys	missense_variant	Exon 1 of 46	1	NM_001457.4	ENSP00000295956.5

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;D;.;.
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.89
MutPred		0.74		Gain of methylation at N27 (P = 0.0053);Gain of methylation at N27 (P = 0.0053);Gain of methylation at N27 (P = 0.0053);Gain of methylation at N27 (P = 0.0053);
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.93
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-57994372;