rs2177153

Variant names:

• chr3-58106619-A-G
• rs2177153
• NM_001457.4:c.1748-61A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001457.4(FLNB):​c.1748-61A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,502,124 control chromosomes in the GnomAD database, including 68,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6787 hom., cov: 31)
  • Exomes 𝑓: 0.29 (61398 hom.)
• Consequence: FLNB NM_001457.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0340
• Publications: 12 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)

ENSG00000303089 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-58106619-A-G is Benign according to our data. Variant chr3-58106619-A-G is described in ClinVar as Benign. ClinVar VariationId is 675060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001457.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	NM_001457.4	MANE Select	c.1748-61A>G		intron	N/A	NP_001448.2
	FLNB	NM_001164317.2		c.1748-61A>G		intron	N/A	NP_001157789.1
	FLNB	NM_001164318.2		c.1748-61A>G		intron	N/A	NP_001157790.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNB	ENST00000295956.9	TSL:1 MANE Select	c.1748-61A>G		intron	N/A	ENSP00000295956.5
	FLNB	ENST00000490882.5	TSL:1	c.1748-61A>G		intron	N/A	ENSP00000420213.1
	FLNB	ENST00000429972.6	TSL:1	c.1748-61A>G		intron	N/A	ENSP00000415599.2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43843 AN: 151836 Hom.: 6766 Cov.: 31

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.299

GnomAD4 exome AF: 0.293 AC: 395180 AN: 1350170 Hom.: 61398 AF XY: 0.292 AC XY: 197661 AN XY: 677960

African (AFR) AF: 0.343 AC: 10663 AN: 31092

American (AMR) AF: 0.160 AC: 7129 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 9810 AN: 25396

East Asian (EAS) AF: 0.0159 AC: 622 AN: 39154

South Asian (SAS) AF: 0.214 AC: 17938 AN: 83914

European-Finnish (FIN) AF: 0.246 AC: 13093 AN: 53194

Middle Eastern (MID) AF: 0.371 AC: 2070 AN: 5578

European-Non Finnish (NFE) AF: 0.314 AC: 316926 AN: 1010692

Other (OTH) AF: 0.299 AC: 16929 AN: 56686

GnomAD4 genome AF: 0.289 AC: 43902 AN: 151954 Hom.: 6787 Cov.: 31 AF XY: 0.284 AC XY: 21085 AN XY: 74260

African (AFR) AF: 0.331 AC: 13690 AN: 41406

American (AMR) AF: 0.215 AC: 3282 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1348 AN: 3470

East Asian (EAS) AF: 0.0222 AC: 115 AN: 5184

South Asian (SAS) AF: 0.184 AC: 882 AN: 4800

European-Finnish (FIN) AF: 0.247 AC: 2609 AN: 10562

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21097 AN: 67938

Other (OTH) AF: 0.302 AC: 638 AN: 2112

Alfa AF: 0.306 Hom.: 25332

Bravo AF: 0.289

Asia WGS AF: 0.115 AC: 404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism (auto)

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: rs2177153; hg19: chr3-58092346;